Methods and compositions for treating schizophrenia

ABSTRACT

The invention relates to methods and compositions for treating schizophrenia or bipolar disorder (in particular, mania) by using a combination of a synaptic vesicle protein 2A (SV2A) inhibitor and an antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and prodrugs thereof. The methods and the compositions can be used for treating one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia or bipolar disorder (in particular, mania).

This application claims priority and benefit from U.S. ProvisionalPatent Application 61/726,440, filed Nov. 14, 2012, the contents anddisclosures of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The invention relates to methods and compositions for treatingschizophrenia or bipolar disorder (in particular, mania). In particular,it relates to the use of a combination of a synaptic vesicle protein 2A(SV2A) inhibitor and an antipsychotic in treating a subject having or atrisk for schizophrenia or bipolar disorder (in particular, mania).

BACKGROUND OF THE INVENTION

Schizophrenia is a chronic psychiatric disorder, characterized by a widespectrum of psychopathology, including positive symptoms such asaberrant or distorted mental representations (e.g., hallucinations,delusions), negative symptoms characterized by diminution of motivationand adaptive goal-directed action (e.g., anhedonia, affectiveflattening, avolition), and cognitive impairment. While abnormalities inthe brain are proposed to underlie the full spectrum of psychopathologyin schizophrenia, currently available antipsychotics are largelyineffective in treating cognitive impairments in schizophrenia patients.

Cognitive impairments in schizophrenia involve both frontal and temporallobe functions that include memory, attention, processing speed, andexecutive control. Recent observations, drawn from preclinical animalmodels and human neuroimaging studies, indicate that altered brainactivity/excitability in the medial temporal lobe memory system maycontribute to cognitive impairment and may also play a role inaugmenting psychotic symptoms due to disinhibition of dopaminergicneurons.

Cognitive deficits are increasingly recognized as a key clinical featurethat can be detected in a prodromal phase and in remission, as well asduring full expression of the illness but are not effectively treated byavailable antipsychotics. Because untreated features of schizophrenia,especially impaired cognition, predict long-term disability in patients(Green et al., Schizophr. Res. 2004, 72, 41-45), it is critical todevelop effective therapies for the spectrum of this illness.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there isprovided a method for treating a subject suffering from schizophrenia orbipolar disorder (in particular, mania), or at risk thereof, the methodcomprising the step of administering to said subject a therapeuticallyeffective amount of an SV2A inhibitor or a pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof in combinationwith a therapeutically effective amount of an antipsychotic or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof. In some embodiments, the methods of the presentinvention treat one or more positive and/or negative symptoms, as wellas cognitive impairment, associated with schizophrenia. In someembodiments, the methods of the present invention treat one or moresymptoms, as well as cognitive impairment, associated with bipolardisorder (in particular, mania). In some embodiments of this invention,the methods of this invention prevent or slow the progression ofcognitive impairment or bipolar disorder (in particular, mania) ofschizophrenia in said subject.

The SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof that is useful in the methods andcompositions of this aspect of the invention include those disclosed in,for example, U.S. patent application Ser. No. 12/580,464 (Pub. No.US-2010-0099735), U.S. patent application Ser. No. 13/287,531 (Pub. No.US-2012-0046336), U.S. patent application Ser. No. 13/370,253 (Pub. No.US-2012-0214859), International Patent Application PCT/US2009/005647(Pub. No. WO2010/044878), International Patent ApplicationPCT/US12/24556 (Pub. No. WO2012/109491), U.S. Patent ProvisionalApplication 61/105,847, 61/152,631, 61/175,536, and 61/441,251. However,any SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof may be used in the methods andcompositions of this aspect of the invention. In other embodiments, theSV2A inhibitor is selected from the group of SV2A inhibitors referred toin International Patent Applications WO2010/144712; WO2010/002869;WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692;WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726; U.S. Pat.Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692 or theirpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs. In other embodiments, the SV2A inhibitor is selected from thegroup consisting of levetiracetam, brivaracetam, and seletracetam orderivatives or analogs or pharmaceutically acceptable salts, hydrates,solvates, polymorphs or prodrugs thereof. In other embodiments, the SV2Ainhibitor is levetiracetam or a derivative or an analog or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof. In other embodiments, the SV2A inhibitor isbrivaracetam or a derivative or an analog or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof. Inother embodiments, the SV2A inhibitor is seletracetam or a derivative oran analog or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof.

The antipsychotic or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof that is useful in the methods andcompositions of this invention include both typical and atypicalantipsychotics.

In some embodiments, the antipsychotics suitable for use in the presentinvention are selected from atypical antipsychotics, including, but notlimited to, those disclosed in, for example, U.S. Pat. Nos. 4,734,416;5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372;4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925, and EPPatents EP402644 and EP368388, and the pharmaceutically acceptablesalts, hydrates, solvates, and polymorphs thereof.

In some embodiments, atypical antipsychotics suitable for use in thepresent invention include, but are not limited to, aripiprazole,asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone,quetiapine, risperidone and ziprasidone, and the pharmaceuticallyacceptable salts, hydrates, solvates, and polymorphs thereof. In someembodiments, the antipsychotic of this invention is selected fromaripiprazole (Bristol-Myers Squibb), olanzapine (Lilly) and ziprasidone(Pfizer), and the pharmaceutically acceptable salts, hydrates, solvates,and polymorphs thereof.

In some embodiments, the antipsychotics suitable for use in the presentinvention are typical antipsychotics, including, but not limited to,acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine,chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine,droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol,heptaminol, isopropamide iodide, levomepromazine, levosulpiride,loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine,penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone,pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl,pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine,thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine,trihexyphenidyl, and zuclopenthixol, and the pharmaceutically acceptablesalts, hydrates, solvates, and polymorphs thereof.

In some embodiments of the present invention, the antipsychotic or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be selected from compounds that are dopaminergicagents (such as dopamine D1 receptor antagonists or agonists, dopamineD₂ receptor antagonists or partial agonists, dopamine D3 receptorantagonists or partial agonists, dopamine D4 receptor antagonists),glutamatergic agents, N-methyl-D-aspartate (NMDA) receptor positiveallosteric modulators, glycine reuptake inhibitors, glutamate reuptakeinhibitor, metabotropic glutamate receptors (mGluRs) agonists orpositive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs),glutamate receptor glur5 positive allosteric modulators (PAMs), M1muscarinic acetylcholine receptor (mAChR) positive allosteric modulators(PAMs), histamine H3 receptor antagonists,α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainatereceptor antagonists, ampakines (CX-516), glutathione prodrugs,noradrenergic agents (such as alpha-2 adrenergic receptor agonists orantagonists and catechol-O-methyl transferase (COMT) inhibitors),serotonin receptor modulators (such as 5-HT_(2A) receptor antagonists,5-HT_(1A) receptor partial agonists, 5-HT₂c agonists, and 5-HT6antagonists), cholinergic agents (such as alpha-7 nicotinic receptoragonists, alpha4-beta2 nicotinic receptor agonists, allostericmodulators of nicotinic receptors and acetylcholinesterase inhibitors,muscarinic receptor agonists and antagonists), cannabinoid CB1antagonists, neurokinin 3 antagonists, neurotensin agonists, monoamineoxidase (MAO) B inhibitors, PDE10 inhibitors, neuronal nitric oxidesynthase (nNOS) inhibitors, neurosteroids, and neurotrophic factors.

In some embodiments, the antipsychotic or a pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof that is useful inthe methods and compositions of this invention include compounds thatmay be used to treat at least one sign or symptom of schizophrenia orbipolar disorder (in particular, mania).

In some embodiments of this aspect of the invention, the antipsychoticis administered at a dose that is subtherapeutic as compared to the doseat which it is therapeutically effective when administered in theabsence of the SV2A inhibitor.

In some embodiments of the invention, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof can be administered at doses as disclosed, for example,in U.S. patent application Ser. No. 12/580,464 (Pub. No.US-2010-0099735), U.S. patent application Ser. No. 13/287,531 (Pub. No.US-2012-0046336), U.S. patent application Ser. No. 13/370,253 (Pub. No.US-2012-0214859), International Patent Application PCT/US2009/005647(Pub. No. WO2010/044878), International Patent ApplicationPCT/US12/24556 (Pub. No. WO2012/109491), U.S. Patent ProvisionalApplication 61/105,847, 61/152,631, 61/175,536, and 61/441,251. In otherembodiments of the invention, the SV2A inhibitor or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of about 0.001 mg/kg to 5 mg/kg. In otherembodiments of the invention, the SV2A inhibitor or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered every 12 or 24 hours at a daily dose of about 0.1 to 5mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0.2 mg/kg, or about 0.01to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, orabout 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.5mg/kg to 5 mg/kg, or about 0.05 mg/kg to 0.5 mg/kg; or at a daily doseof 0.0015-7 mg/kg, 0.0015-5 mg/kg, 0.01-5 mg/kg, 0.05-4.0 mg/kg, 0.05-2mg/kg, 0.05-1.5 mg/kg, 0.1-1 mg/kg, 1-5 mg/kg, 1.5-4 mg/kg, or 1.8-3.6mg/kg. In other embodiments of this aspect of the invention, the SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered every 12 or 24 hours at adaily dose of about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, orabout 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about2.0 to 4.0 mg/kg, or about 2.0 to 3.0 mg/kg, or about 3.0 to 4.0 mg/kg,or about 0.2 to 0.4 mg/kg, or about 0.2 to 0.3 mg/kg, or about 0.3 to0.4 mg/kg, or about 0.001-5 mg/kg, or about 0.001-0.5 mg/kg, or about0.01-0.5 mg/kg. In some embodiments, the SV2A inhibitor may be selectedfrom the group consisting of levetiracetam, brivaracetam, andseletracetam or derivatives or analogs or pharmaceutically acceptablesalts, hydrates, solvates, polymorphs or prodrugs, polymorphs, orprodrugs thereof, said SV2A inhibitor being administered every 12 or 24hours at a daily dose selected from any of the above. In someembodiments, a subtherapeutic amount of the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate or polymorph, orprodrug thereof is used. Such subtherapeutic amount, may be, forexample, a daily dose of less than 7 mg/kg, less than 6 mg/kg, less than5 mg/kg, less than 4 mg/kg, less than 3.8 mg/kg, less than 3.6 mg/kg,less than 3.4 mg/kg, less than 3.2 mg/kg, less than 3 mg/kg, less than2.9 mg/kg, less than 2.8 mg/kg, less than 2.7 mg/kg, less than 2.6mg/kg, less than 2.5 mg/kg, less than 2.4 mg/kg, less than 2.3 mg/kg,less than 2.2 mg/kg, less than 2.1 mg/kg, less than 2 mg/kg, less than1.5 mg/kg, less than 1 mg/kg, less than 0.5 mg/kg, less than 0.1 mg/kg,less than 0.05 mg/kg, less than 0.01 mg/kg, or less than 0.0015 mg/kg;or less than 500 mg, less than 420 mg, less than 400 mg, less than 350mg, less than 300 mg, less than 280 mg, less than 270 mg, less than 260mg, less than 250 mg, less than 240 mg, less than 230 mg, less than 225mg, less than 220 mg, less than 210 mg, less than 200 mg, less than 190mg, less than 180 mg, less than 175 mg, less than 170 mg, less than 150mg, less than 140 mg, less than 125 mg, less than 120 mg, less than 110mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg,less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, lessthan 60 mg, less than 55 mg, less than 50 mg, less than 45 mg, less than40 mg, less than 35 mg, less than 30 mg, less than 28 mg, less than 25mg, less than 20 mg, less than 15 mg, less than 12 mg, less than 10 mg,less than 9 mg, less than 8 mg, less than 7 mg, less than 6 mg, lessthan 5.5 mg, less than 5 mg, less than 4.2 mg, less than 3.5 mg, lessthan 3 mg, less than 2.8 mg, less than 2.5 mg, less than 2.0 mg, lessthan 1.5 mg, less than 0.7 mg, less than 0.35 mg, less than 0.18 mg,less than 0.15 mg, or less than 0.1 mg is administered. The SV2Ainhibitors that can be used in the foregoing embodiments include, forexample, levetiracetam, brivaracetam, and seletracetam or theirpharmaceutically acceptable salt, hydrate, solvate or polymorph, orprodrug thereof.

In some embodiments, the SV2A inhibitor present in the composition ofthis invention is administered at a daily dose of 0.0015 to 7 mg/kg/day(which, given a typical human subject of 70 kg, is about 0.1-500mg/day). Daily doses that may be used include, but are not limited to0.0015 mg/kg, 0.002 mg/kg, 0.0025 mg/kg, 0.005 mg/kg, 0.01 mg/kg, 0.02mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg, 0.08mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.2 mg/kg,1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, 2.2 mg/kg, 2.4mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.5 mg/kg, 4.0 mg/kg,4.5 mg/kg, 5.0 mg/kg, 6.0 mg/kg, or 7.0 mg/kg; or 0.1 mg, 0.15 mg, 0.18mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg, 2.8 mg, 3.0 mg, 3.5 mg, 4.2mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg,25 mg, 28 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 70 mg, 75mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 140 mg,150 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 225 mg, 250 mg,280 mg, 300 mg, 350 mg, 400 mg, or 500 mg, or within the range of0.0015-5 mg/kg, 0.01-0.8 mg/kg, 0.01-1 mg/kg, 0.01-1.5 mg/kg, 0.01-2mg/kg, 0.01-2.5 mg/kg, 0.01-3 mg/kg, 0.01-3.5 mg/kg, 0.01-4 mg/kg,0.01-5 mg/kg, 0.025-0.8 mg/kg, 0.025-1 mg/kg, 0.025-1.5 mg/kg, 0.025-2mg/kg, 0.025-2.5 mg/kg, 0.025-3 mg/kg, 0.025-3.5 mg/kg, 0.025-4 mg/kg,0.05-0.8 mg/kg, 0.05-1 mg/kg, 0.05-1.5 mg/kg, 0.05-2 mg/kg, 0.05-2.5mg/kg, 0.05-3 mg/kg, 0.05-3.5 mg/kg, 0.05-4 mg/kg, 0.075-0.8 mg/kg,0.075-1 mg/kg, 0.075-1.5 mg/kg, 0.075-2 mg/kg, 0.075-2.5 mg/kg, 0.075-3mg/kg, 0.075-3.5 mg/kg, 0.075-4 mg/kg, 0.1-0.8 mg/kg, 0.1-1 mg/kg,0.1-1.5 mg/kg, 0.1-2 mg/kg, 0.1-2.5 mg/kg, 0.1-3 mg/kg, 0.1-3.5 mg/kg,0.1-4 mg/kg, 0.2-0.8 mg/kg, 0.2-1 mg/kg, 0.2-1.5 mg/kg, 0.2-2 mg/kg,0.2-2.5 mg/kg, 0.2-3 mg/kg, 0.2-3.5 mg/kg, 0.2-4 mg/kg, 0.5-0.8 mg/kg,0.5-1 mg/kg, 0.5-1.5 mg/kg, 0.5-2 mg/kg, 0.5-2.5 mg/kg, 0.5-3 mg/kg,0.5-3.5 mg/kg, or 0.5-4 mg/kg; or within the range of 0.7-50 mg, 0.7-75mg, 0.7-100 mg, 0.7-150 mg, 0.7-180 mg, 0.7-225 mg, 0.7-250 mg, 0.7-280mg, 1.8-50 mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg, 1.8-180 mg, 1.8-225mg, 1.8-250 mg, 1.8-280 mg, 3.5-50 mg, 3.5-75 mg, 3.5-100 mg, 3.5-150mg, 3.5-180 mg, 3.5-225 mg, 3.5-250 mg, 3.5-280 mg, 5-50 mg, 5-75 mg,5-100 mg, 5-150 mg, 5-180 mg, 5-225 mg, 5-250 mg, 5-280 mg, 7-50 mg,7-75 mg, 7-100 mg, 7-150 mg, 7-180 mg, 7-225 mg, 7-250 mg, 7-280 mg,15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg, 15-225 mg, 15-250mg, 15-280 mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150 mg, 35-180 mg,35-225 mg, 35-250 mg, or 35-280 mg. In some embodiments, thelevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is present in the composition of thisinvention in an amount of 0.7-50 mg, 0.7-75 mg, 0.7-100 mg, 0.7-150 mg,0.7-180 mg, 0.7-225 mg, 0.7-250 mg, 0.7-280 mg, 1.8-50 mg, 1.8-75 mg,1.8-100 mg, 1.8-150 mg, 1.8-180 mg, 1.8-225 mg, 1.8-250 mg, 1.8-280 mg,3.5-50 mg, 3.5-75 mg, 3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-225 mg,3.5-250 mg, 3.5-280 mg, 5-50 mg, 5-75 mg, 5-100 mg, 5-150 mg, 5-180 mg,5-225 mg, 5-250 mg, 5-280 mg, 7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg,7-180 mg, 7-225 mg, 7-250 mg, 7-280 mg, 15-50 mg, 15-75 mg, 15-100 mg,15-150 mg, 15-180 mg, 15-225 mg, 15-250 mg, 15-280 mg, 35-50 mg, 35-75mg, 35-100 mg, 35-150 mg, 35-180 mg, 35-225 mg, 35-250 mg, or 35-280 mg;or 0.1 mg, 0.15 mg, 0.18 mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg,2.8 mg, 3.0 mg, 3.5 mg, 4.2 mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 8 mg, 9 mg,10 mg, 12 mg, 15 mg, 20 mg, 25 mg, 28 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50mg, 55 mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110mg, 120 mg, 125 mg, 140 mg, 150 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200mg, 210 mg, 225 mg, 250 mg, 280 mg, 300 mg, 350 mg, 400 mg, or 500 mg.In some embodiments, a subtherapeutic amount of the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate or polymorph, orprodrug thereof is used. The SV2A inhibitors that can be used in theforegoing embodiments include, for example, levetiracetam, brivaracetam,and seletracetam or their pharmaceutically acceptable salt, hydrate,solvate or polymorph, or prodrug thereof.

In some embodiments, the SV2A inhibitor present in the composition ofthis invention is levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof and is administered ataccording to one of the daily dose ranges indicated as “+” listed inTable 1 or Table 2. In some embodiments, the levetiracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in the composition of this invention in anamount of about 70 to 140 mg, or about 7 to 180 mg, or about 25 to 180mg, or about 40 to 130 mg, or about 140 to 300 mg, or about 200 to 300mg, or about 140 to 200 mg, or about 7 to 350 mg, about 70-350 mg, about100-300 mg, or about 125-250 mg. In some embodiments, a subtherapeuticamount of levetiracetam or a pharmaceutically acceptable salt, hydrate,solvate or polymorph, or prodrug thereof is used.

In some embodiments, the SV2A inhibitor present in the composition ofthis invention is brivaracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof and is administered ataccording to one of the daily dose ranges indicated as “+” listed inTables 3-6. In some embodiments, the brivaracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof ispresent in the composition of this invention in an amount of about 7 to15 mg, or about 0.7 to 180 mg, or about 2.5 to 180 mg, or about 4.0 to130 mg, or about 14 to 30 mg, or about 0.1-35 mg, 0.5-35 mg, 0.75-35 mg,1.0-35 mg, 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1-15mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5 mg, or 0.7-50 mg, 0.7-75 mg, 0.7-100mg, 0.7-150 mg, 0.7-180 mg, 0.7-225 mg, 0.7-250 mg, 0.7-280 mg, 1.8-50mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg, 1.8-180 mg, 1.8-225 mg, 1.8-250mg, 1.8-280 mg, 3.5-50 mg, 3.5-75 mg, 3.5-100 mg, 3.5-150 mg, 3.5-180mg, 3.5-225 mg, 3.5-250 mg, 3.5-280 mg, 5-50 mg, 5-75 mg, 5-100 mg,5-150 mg, 5-180 mg, 5-225 mg, 5-250 mg, 5-280 mg, 7-50 mg, 7-75 mg,7-100 mg, 7-150 mg, 7-180 mg, 7-225 mg, 7-250 mg, 7-280 mg, 15-50 mg,15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg, 15-225 mg, 15-250 mg, 15-280mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150 mg, 35-180 mg, 35-225 mg,35-250 mg, or 35-280 mg. In some embodiments, a subtherapeutic amount ofbrivaracetam or a pharmaceutically acceptable salt, hydrate, solvate orpolymorph, or prodrug thereof is used.

In some embodiments, the SV2A inhibitor present in the composition ofthis invention is seletracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof and is administered ataccording to one of the daily dose ranges indicated as “+” listed inTables 7-10. In some embodiments, the seletracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof ispresent in the composition of this invention in an amount of about 7 to15 mg, or about 0.7 to 180 mg, or about 2.5 to 180 mg, or about 4.0 to130 mg, or about 14 to 30 mg, or about 0.1-35 mg, 0.5-35 mg, 0.75-35 mg,1.0-35 mg, 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1-15mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5 mg, or 0.7-50 mg, 0.7-75 mg, 0.7-100mg, 0.7-150 mg, 0.7-180 mg, 0.7-225 mg, 0.7-250 mg, 0.7-280 mg, 1.8-50mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg, 1.8-180 mg, 1.8-225 mg, 1.8-250mg, 1.8-280 mg, 3.5-50 mg, 3.5-75 mg, 3.5-100 mg, 3.5-150 mg, 3.5-180mg, 3.5-225 mg, 3.5-250 mg, 3.5-280 mg, 5-50 mg, 5-75 mg, 5-100 mg,5-150 mg, 5-180 mg, 5-225 mg, 5-250 mg, 5-280 mg, 7-50 mg, 7-75 mg,7-100 mg, 7-150 mg, 7-180 mg, 7-225 mg, 7-250 mg, 7-280 mg, 15-50 mg,15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg, 15-225 mg, 15-250 mg, 15-280mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150 mg, 35-180 mg, 35-225 mg,35-250 mg, or 35-280 mg. In some embodiments, a subtherapeutic amount ofseletracetam or a pharmaceutically acceptable salt, hydrate, solvate orpolymorph, or prodrug thereof is used.

In some embodiments of the invention, the SV2A inhibitor and theantipsychotic, or their pharmaceutically acceptable salts, hydrates,solvates, polymorphs, or prodrugs are administered simultaneously, orsequentially, or in a single formulation, or in separate formulationspackaged together. In other embodiments, the SV2A inhibitor and theantipsychotic, or their pharmaceutically acceptable salts, hydrates,solvates, polymorphs, or prodrugs are administered via different routes.As used herein, “combination” includes administration by any of theseformulations or routes of administration.

In some embodiments of the invention, the combined treatment has alonger or improved therapeutic effect in the subject than is attained byadministering the antipsychotic or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in the absence of theSV2A inhibitor or a pharmaceutically acceptable salt, solvate, hydrate,polymorph, or prodrug thereof by at least about 1.5×, or 2.0×, or 2.5×,or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×,or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greaterthan about 10×.

In some embodiments of the invention, the combined treatment has alonger or improved therapeutic effect in the subject than is attained byadministering the SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in the absence of theantipsychotic or a pharmaceutically acceptable salt, solvate, hydrate,polymorph, or prodrug thereof by at least about 1.5×, or 2.0×, or 2.5×,or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×,or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greaterthan about 10×.

In accordance with another aspect of the present invention, there isprovided a method of increasing the therapeutic index of anantipsychotic or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in a method of treating schizophrenia orbipolar disorder (in particular, mania) in a subject in need or at riskthereof, comprising administering an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in combination with the antipsychotic or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof to said subject.

In some embodiments, the increase in the therapeutic index of theantipsychotic or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is greater than the therapeutic index ofthe antipsychotic or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof when administered in the absenceof the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof by at least about 1.5×, or 2.0×,or 2.5×, or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×,or 6.5×, or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×,or greater than about 10×.

In accordance with another aspect of the present invention, there isprovided a method of increasing the therapeutic index of an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in a method of treating schizophrenia orbipolar disorder (in particular, mania) in a subject in need or at riskthereof, comprising administering the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in combination with an antipsychotic or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof to said subject.

In some embodiments, the increase in the therapeutic index of the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is greater than the therapeutic index ofthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof when administered in the absenceof the antipsychotic or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof by at least about 1.5×, or 2.0×,or 2.5×, or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×,or 6.5×, or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×,or greater than about 10×.

In accordance with another aspect of this invention, there is provided apharmaceutical composition for treating a subject suffering fromschizophrenia or bipolar disorder (in particular, mania), or at riskthereof, the composition comprising an SV2A inhibitor and anantipsychotic or their pharmaceutically acceptable salts, hydrates,solvates, polymorphs, or prodrugs thereof. In some embodiments, thecomposition of this invention is for treating one or more positiveand/or negative symptoms, as well as cognitive impairment, associatedwith schizophrenia. In some embodiments, the composition of thisinvention is for treating one or more symptoms, as well as cognitiveimpairment, associated with bipolar disorder (in particular, mania). Insome embodiments, the composition is in a solid form (e.g., capsule ortablet). In some embodiments, the composition is in a liquid form. Insome embodiments, the composition is in an aqueous solution. In someembodiments, the composition is in a suspension form. In someembodiments, the composition is in a sustained release form, or acontrolled release form, or a delayed release form, or an extendedrelease form. In some embodiments, the composition is in a unit dosageform. In other embodiments, the two components of the compositions arein separate delivery forms packaged together. In some embodiments, thecomposition is for oral administration. In some embodiments, thecomposition is in a unit dosage form. In some embodiments, thecomposition is administered once daily. In some embodiments, thecomposition is administered twice daily.

In some embodiments, both the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof and theantipsychotic or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof are in an extended release form present inthe composition. In some embodiments, both the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof and the antipsychotic or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof are not in anextended release form present in the composition. In some embodiments,the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof present in the composition is inan extended release form, while the antipsychotic or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof present in the composition is not in an extended releaseform. For example, the antipsychotic or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof is in an immediaterelease form. In some embodiments, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof present in the composition is not in an extended releaseform, while the antipsychotic or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof present in thecomposition is in an extended release form. For example, the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is in an immediate release form. In someembodiments, the extended release SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof presentin the composition does not affect the pharmacokinetics or the half-lifeclearance of the antipsychotics or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof present in the samecomposition. In some embodiments, the extended release antipsychotics orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof present in the composition does not affect thepharmacokinetics or the half-life clearance of SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof present in the same composition. In some embodiments,the extended release form SV2A inhibitor includes without limitation acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form. In someembodiments, the extended release form antipsychotics includes withoutlimitation a controlled release form, a prolonged release form, asustained release form, a delayed release form, or a slow release form.The SV2A inhibitor that can be used in the composition according to theforegoing embodiments include, without limitation, levetiracetam,brivaracetam, seletracetam and their pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof.

In some embodiments of this invention, the composition compriseslevetiracetam, brivaracetam, seletracetam, or a derivative or an analogor a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof and an antipsychotic or a derivative or an analog or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof.

In some embodiments of this invention, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in the composition is present in an amount of 0.07-350mg, or 50-250 mg, 3-50 mg, 0.1-500 mg, 0.1-350 mg, 0.7-350 mg, 3-300 mg,3-150 mg, 3-110 mg, 7-70 mg, 70-350 mg, 100-300 mg, or 125-250 mg. Insome embodiments, the SV2A inhibitor or a pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof is present in anamount less than 500 mg, less than 350 mg, less than 300 mg, less than250 mg, less than 200 mg, less than 150 mg, less than 110 mg, less than100 mg, less than 70 mg, less than 50 mg, less than 35 mg, less than 10mg, less than 7 mg, less than 5 mg, less than 3 mg, less than 1 mg, lessthan 0.7 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, orless than 0.05 mg. In certain embodiments of this aspect of theinvention, the SV2A inhibitor is present in an amount of 0.07-60 mg,0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg, 5-140 mg, 0.7-180 mg,125-240 mg, 3-50 mg, or 3-60 mg. In other embodiments of this aspect ofthe invention, the SV2A inhibitor is present in an amount of 0.05-35 mg.In some embodiments of the composition of this invention, the SV2Ainhibitor may be selected from the group consisting of levetiracetam,brivaracetam, and seletracetam or derivatives or analogs orpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs thereof, said SV2A inhibitor being present in an amountselected from any of the above.

In some embodiments, the effect of the treatment is measured bydetecting the difference between the levels of reelin in the subjectprior to and after the administration step.

In some embodiments, the effect of the treatment is measured bydetecting the difference between the levels of somatostatin in thesubject prior to and after the administration step.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts increased mRNA expression of the gene encoding SV2A inthe dentate gyms of the hippocampus of aged-impaired rats (AI) ascompared to young rats (Y) and aged-unimpaired rats (AU). NormalizedAffymetrix GeneChip probe set signal values (Y-axis), as a measure ofmRNA expression, are plotted against learning indices of different rats,as a measure of cognitive impairment.

FIG. 2 depicts the effects of administering levetiracetam on the spatialmemory retention of six aged-impaired rats (AI) in a Morris Water Maze(MWM) test. Three treatment conditions are employed: vehicle control,levetiracetam (5 mg/kg/day) and levetiracetam (10 mg/kg/day). The AIrats are trained for two consecutive days, with a one-time treatmentprior to the training trials per day. 24 hours later, the AI rats aretested. The time the AI rats, 24 hours after treatment with thedifferent conditions and two days of training, spent swimming in thetarget quadrant or the target annulus in a memory retention trial isused as a measure of spatial memory retention. The target quadrantrefers to the quadrant of the maze (which is a circular pool) where theescape platform is placed during the training trials. The target annulusrefers to the exact location of the escape platform during the trainingtrials.

FIG. 3 depicts the effects of administering levetiracetam on the spatialmemory retention of ten aged-impaired rats (AI) in an eight-arm RadialArm Maze (RAM) test. Six treatment conditions are employed: vehiclecontrol, levetiracetam (1.25 mg/kg), levetiracetam (2.5 mg/kg),levetiracetam (5 mg/kg), levetiracetam (10 mg/kg) and levetiracetam (20mg/kg). In the RAM task used, there is a one-hour delay betweenpresentation of a subset of arms (5 arms available and 3 arms blocked)and completion of the eight-arm win-shift task (eight arms available).

Rats are pre-treated 30-40 minutes before daily trials with a one-timedrug/control treatment. The number of errors made by the rats after thedelay is used as a measure of spatial memory retention. Errors aredefined as instances when rats enter an arm from which food has alreadybeen retrieved in the pre-delay component of the trial or when ratsre-visit an arm in the post-delay session that has already been visited.Paired t-tests are used to compare the number of errors betweendifferent doses of levetiracetam and vehicle control.

FIG. 4 depicts the effects of administering levetiracetam or valproateseparately on the spatial memory retention of ten aged-impaired rats(AI) in an eight-arm Radial Arm Maze (RAM) test.

FIG. 5 depicts the effects of administering levetiracetam or valproatein combination on the spatial memory retention of ten aged-impaired rats(AI) in an eight-arm Radial Arm Maze (RAM) test.

FIG. 6 shows an isobologram plotting levetiracetam dose againstvalproate dose. The diagonal straight line is the line of additivity,anchored on each axis by the lowest effective doses of valproate andlevetiracetam when assessed individually.

FIG. 7 depicts the experimental design of the human trials forlevetiracetam treatment.

FIG. 8A depicts the average activity in the left CA3 of aMCI subjectswith placebo treatment and age-matched control subjects with placebotreatment during the presentation of lure stimuli that the subjectcorrectly identified as “similar.”

FIG. 8B depicts the average activity in the left CA3 of aMCI subjectswith placebo treatment or levetiracetam treatment (125 mg twice a dayfor two weeks) during the presentation of lure stimuli that the subjectcorrectly identified as “similar.”

FIG. 8C is a table of the data represented in FIGS. 8A and 8B.

FIG. 9A depicts the average activity in the left entorhinal cortex ofage-matched control subjects with placebo treatment and aMCI subjectswith placebo treatment during the presentation of lure stimuli that thesubject correctly identify as “similar.”

FIG. 9B depicts the average activity in the left entorhinal cortex ofthe same aMCI subjects with placebo treatment or levetiracetam treatment(125 mg twice a day for two weeks) during the presentation of lurestimuli that the subject correctly identify as “similar.”

FIG. 9C is a table of the data represented in FIGS. 9A and 9B.

FIG. 10A depicts an example of the sequence of images shown to subjectsin the explicit 3-alternative forced choice task described in Example 2.

FIG. 10B shows sample pairs of similar (“lure”) images.

FIG. 11 shows the difference between the aMCI (placebo) subjects andage-matched control (placebo) subjects in their performance of theexplicit 3-alternative forced choice task described in Example 2. Eachbar represents the proportion of the subject responses (old, similar, ornew) when presented with a lure image.

FIG. 12 shows the difference between the same aMCI subjects with placebotreatment or with levetiracetam treatment (125 mg twice a day for twoweeks) in their performance of the explicit 3-alternative forced choicetask described in Example 2. Each bar represents the proportion of thesubjects responses (old, similar, or new) when presented with a lureimage.

FIG. 13 is a table of the data represented in FIGS. 11 and 12.

FIG. 14A shows the difference between the age-matched control (placebo)subjects and the aMCI subjects treated with placebo or withlevetiracetam (125 mg twice a day for two weeks) in their performance ofthe Buschke Selective reminding Test—Delayed Recall.

FIG. 14B is a table of the data represented in FIG. 14A.

FIG. 15A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Benton VisualRetention Test.

FIG. 15B is a table of the data represented in FIG. 15A.

FIG. 16A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Verbal PairedAssociates Test—Recognition.

FIG. 16B is a table of the data represented in FIG. 16A.

FIG. 17A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Verbal PairedAssociates Test—Delayed Recall.

FIG. 17B is a table of the data represented in FIG. 17A.

FIG. 18A is a table showing the subject selection process for the humanlevetiracetam trial described in Example 2.

FIG. 18B is a table showing the characteristics of the subjects selectedfor the human levetiracetam trial described in Example 2.

FIG. 19 depicts the effects of administering brivaracetam on the memoryperformance of nine aged-impaired rats in an eight-arm Radial Arm Mazetask. Doses of brivaracetam administered to the AI rats include 0.0625mg/kg, 0.125 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg.Means and SEMs for the number of errors are shown as the y-axis.

FIG. 20 depicts the effects of administering seletracetam on the memoryperformance of nine aged-impaired rats in an eight-arm Radial Arm Mazetest. Doses of seletracetam administered to the AI rats include 0.0625mg/kg, 0.125 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg.Means and SEMs for the number of errors are shown as the y-axis.

FIG. 21A and FIG. 21B depict the performance of aged-impaired rats(n=3/group) treated with brivaracetam at a dose of 2 mg/kg/day after 14days in the water maze task. Rats treated with brivaracetam at 2mg/kg/day (t(2)=10.000, p=0.010) but not vehicle (t(2)=1.964, p=0.188)show a significant spatial bias for the target quadrant compared to theother controls quadrants. Brivaracetam-treated rats (2 mg/kg/day) alsospend significantly more time in the target quadrant than thevehicle-treated rats, t(4)=3.881, p=0.018. Brivaracetam-treated rats (2mg/kg/day) spend significantly more time in the target annulus (areasurrounding the location of the escape platform) than thevehicle-treated rats, t(4)=3.109, p=0.036.

FIG. 22A and FIG. 22B depict the effects of levetiracetam on fMRIactivities in Dentate Gyrus/CA3 region of aMCI patients at a dose of62.5 mg BID and 250 mg BID.

FIG. 23A and FIG. 23B show the difference between the aMCI (placebo)subjects and age-matched control (placebo) subjects in their performanceof the explicit 3-alternative forced choice task described in Example 4at a dose of 62.5 mg BID placebo and 250 mg BID placebo. Each barrepresents the proportion of the subject responses (old, similar, ornew) when presented with a lure image.

FIG. 24A and FIG. 24B show the difference between the same aMCI subjectswith placebo treatment or with levetiracetam treatment (62.5 mg BID and250 mg BID) in their performance of the explicit 3-alternative forcedchoice task described in Example 4. Each bar represents the proportionof the subjects responses (old, similar, or new) when presented with alure image.

FIG. 25 shows that administering levetiracetam at a dose of 10 mg/kg/dayand vehicle in osmotic minipumps for four weeks in aged-impaired ratsrestores sematostatin in DG hilus.

FIG. 26 shows that administering levetiracetam at a dose of 10 mg/kg/dayand vehicle in osmotic minipumps for four weeks in aged-impaired ratsrestores reelin in Entorhinal Cortex (EC2).

FIGS. 27A-27C depict the levetiracetam blood plasma levels for the aMCIpatients at a dose of 62.5 mg BID, 125 mg BID and 250 mg BIDlevetiracetam.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. Generally, nomenclature used inconnection with, and techniques of, cell and tissue culture, molecularbiology, cell and cancer biology, neurobiology, neurochemistry,virology, immunology, microbiology, pharmacology, genetics and proteinand nucleic acid chemistry, described herein, are those well known andcommonly used in the art.

The methods and techniques of the present invention are generallyperformed, unless otherwise indicated, according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout thisspecification. See, e.g. “Principles of Neural Science”, McGraw-HillMedical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”,Oxford University Press, Inc. (1995); Lodish et al., “Molecular CellBiology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths etal., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co.,N.Y. (1999); Gilbert et al., “Developmental Biology, 6th ed.”, SinauerAssociates, Inc., Sunderland, Mass. (2000).

Chemistry terms used herein are used according to conventional usage inthe art, as exemplified by “The McGraw-Hill Dictionary of ChemicalTerms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

All of the above, and any other publications, patents and publishedpatent applications referred to in this application are specificallyincorporated by reference herein. In case of conflict, the presentspecification, including its specific definitions, will control.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer (or components) or group of integers (or components),but not the exclusion of any other integer (or components) or group ofintegers (or components).

The singular forms “a,” “an,” and “the” include the plurals unless thecontext clearly dictates otherwise.

The term “including” is used to mean “including but not limited to”.“Including” and “including but not limited to” are used interchangeably.

The term “agent” is used herein to denote a chemical compound (such asan organic or inorganic compound, a mixture of chemical compounds), abiological macromolecule (such as a nucleic acid, an antibody, includingparts thereof as well as humanized, chimeric and human antibodies andmonoclonal antibodies, a protein or portion thereof, e.g., a peptide, alipid, a carbohydrate), or an extract made from biological materialssuch as bacteria, plants, fungi, or animal (particularly mammalian)cells or tissues. Agents include, for example, agents which are knownwith respect to structure, and those which are not known with respect tostructure.

A “patient”, “subject”, or “individual” are used interchangeably andrefer to either a human or a non-human animal. These terms includemammals, such as humans, primates, livestock animals (including bovines,porcines, etc.), companion animals (e.g., canines, felines, etc.) androdents (e.g., mice and rats).

“Cognitive function” or “cognitive status” refers to any higher orderintellectual brain process or brain state, respectively, involved inlearning and/or memory including, but not limited to, attention,information acquisition, information processing, working memory,short-term memory, long-term memory, anterograde memory, retrogradememory, memory retrieval, discrimination learning, decision-making,inhibitory response control, attentional set-shifting, delayedreinforcement learning, reversal learning, the temporal integration ofvoluntary behavior, expressing an interest in one's surroundings andself-care, speed of processing, reasoning and problem solving and socialcognition.

In humans, cognitive function may be measured, for example and withoutlimitation, by the clinical global impression of change scale(CIBIC-plus scale); the Mini Mental State Exam (MMSE); theNeuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale(CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB);the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke SelectiveReminding Test (Buschke and Fuld, 1974); the Verbal Paired Associatessubtest; the Logical Memory subtest; the Visual Reproduction subtest ofthe Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the BentonVisual Retention Test, or the explicit 3-alternative forced choice task,or MATRICS consensus neuropsychological test battery. See Folstein etal., J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger etal., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002and Masur et al., 1994. Also see Buchanan, R. W., Keefe, R. S. E.,Umbricht, D., Green, M. F., Laughren, T., and Marder, S. R. (2011), TheFDA-NIMH-MATRICS guidelines for clinical trial design ofcognitive-enhancing drugs: what do we know 5 years later? Schizophr.Bull. 37, 1209-1217.

In animal model systems, cognitive function may be measured in variousconventional ways known in the art, including using a Morris Water Maze(MWM), Barnes circular maze, elevated radial arm maze, T maze or anyother mazes in which the animals use spatial information. Cognitivefunction can be assessed by reversal learning, extradimensional setshifting, conditional discrimination learning and assessments of rewardexpectancy. Other tests known in the art may also be used to assesscognitive function, such as novel object recognition and odorrecognition tasks.

Cognitive function may also be measured using imaging techniques such asPositron Emission Tomography (PET), functional magnetic resonanceimaging (fMRI), Single Photon Emission Computed Tomography (SPECT), orany other imaging technique that allows one to measure brain function.In animals, cognitive function may also be measured withelectrophysiological techniques.

“Promoting” cognitive function refers to affecting impaired cognitivefunction so that it more closely resembles the function of a normal,unimpaired subject. Cognitive function may be promoted to any detectabledegree, but in humans preferably is promoted sufficiently to allow animpaired subject to carry out daily activities of normal life at thesame level of proficiency as a normal, unimpaired subject.

“Preserving” cognitive function refers to affecting normal or impairedcognitive function such that it does not decline or does not fall belowthat observed in the subject upon first presentation or diagnosis, ordelays such decline.

“Improving” cognitive function includes promoting cognitive functionand/or preserving cognitive function in a subject.

“Cognitive impairment” refers to cognitive function in subjects that isnot as robust as that expected in a normal, unimpaired subject. In somecases, cognitive function is reduced by about 5%, about 10%, about 30%,or more, compared to cognitive function expected in a normal, unimpairedsubject. In other cases, “cognitive impairment” in subjects affected byschizophrenia or bipolar disorder (in particular, mania) refers tocognitive function in subjects that is not as robust as that expected innormal, unimpaired subject.

“Schizophrenia” refers to a chronic debilitating disorder, characterizedby a spectrum of psychopathology, including positive symptoms such asaberrant or distorted mental representations (e.g., hallucinations,delusions), negative symptoms characterized by diminution of motivationand adaptive goal-directed action (e.g., anhedonia, affectiveflattening, avolition), and cognitive impairment. While abnormalities inthe brain are proposed to underlie the full spectrum of psychopathologyin schizophrenia, currently available antipsychotics are largelyineffective in treating cognitive impairments in patients.

“Bipolar disorder” or “BP” or “manic depressive disorder” or “manicdepressive illness” refers to a chronic psychological/mood disorderwhich can be characterized by significant mood changes including periodsof depression and euphoric manic periods. BP may be diagnosed by askilled physician based on personal and medical history, interviewconsultation and physical examinations. The term “mania” or “manicperiods” or other variants refers to periods where an individualexhibits some or all of the following characteristics: racing thoughts,rapid speech, elevated levels of activity and agitation as well as aninflated sense of self-esteem, euphoria, poor judgment, insomnia,impaired concentration and aggression.

“Treating” a condition or patient refers to taking steps to obtainbeneficial or desired results, including clinical results. Beneficial ordesired clinical results include, but are not limited to, preventing orslowing the progression of the disease or disorder, or alleviation,amelioration, or slowing the progression, of one or more symptomsassociated with CNS disorders with cognitive impairment, such asschizophrenia or bipolar disorder (in particular, mania).

“Treating cognitive impairment” refers to taking steps to improvecognitive function in a subject with cognitive impairment so that thesubject's performance in one or more cognitive tests is improved to anydetectable degree, or is prevented from further decline. Preferably,that subject's cognitive function, after treatment of cognitiveimpairment, more closely resembles the function of a normal, unimpairedsubject. Treatment of cognitive impairment in humans may improvecognitive function to any detectable degree, but is preferably improvedsufficiently to allow the impaired subject to carry out daily activitiesof normal life at the same level of proficiency as a normal, unimpairedsubject. In some cases, “treating cognitive impairment” refers to takingsteps to improve cognitive function in a subject with cognitiveimpairment so that the subject's performance in one or more cognitivetests is improved to any detectable degree, or is prevented from furtherdecline. Preferably, that subject's cognitive function, after treatmentof cognitive impairment, more closely resembles the function of anormal, unimpaired subject. In some cases, “treating cognitiveimpairment” in a subject affecting by schizophrenia or bipolar disorder(in particular, mania) refers to takings steps to improve cognitivefunction in the subject so that the subject's cognitive function, aftertreatment of cognitive impairment, more closely resembles the functionof a normal, unimpaired subject.

“Administering” or “administration of” a substance, a compound or anagent to a subject can be carried out using one of a variety of methodsknown to those skilled in the art. For example, a compound or an agentcan be administered, intravenously, arterially, intradermally,intramuscularly, intraperitonealy, intravenously, subcutaneously,ocularly, sublingually, orally (by ingestion), intranasally (byinhalation), intraspinally, intracerebrally, and transdermally (byabsorption, e.g., through a skin duct). A compound or agent can alsoappropriately be introduced by rechargeable or biodegradable polymericdevices or other devices, e.g., patches and pumps, or formulations,which provide for the extended, slow, or controlled release of thecompound or agent. Administering can also be performed, for example,once, a plurality of times, and/or over one or more extended periods. Insome aspects, the administration includes both direct administration,including self-administration, and indirect administration, includingthe act of prescribing a drug. For example, as used herein, a physicianwho instructs a patient to self-administer a drug, or to have the drugadministered by another and/or who provides a patient with aprescription for a drug is administering the drug to the patient.

Appropriate methods of administering a substance, a compound or an agentto a subject will also depend, for example, on the age of the subject,whether the subject is active or inactive at the time of administering,whether the subject is cognitively impaired at the time ofadministering, the extent of the impairment, and the chemical andbiological properties of the compound or agent (e.g. solubility,digestibility, bioavailability, stability and toxicity). In someembodiments, a compound or an agent is administered orally, e.g., to asubject by ingestion, or intravenously, e.g., to a subject by injection.In some embodiments, the orally administered compound or agent is in anextended release or slow release formulation, or administered using adevice for such slow or extended release.

“SV2A inhibitor” refers to any agent, substance or compound that bindsto SV2A and reduces synaptic function by reducing pre-synaptic vesiclerelease (See, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al.2004; Gillard et al. 2006; Custer et al., 2006; Smedt et al., 2007; Yanget al., 2007; Meehan, “Levetiracetam has an activity-dependent effect oninhibitory transmission,” Epilepsia, 2012 Jan. 31; and Example 8 of WO2001/62726, all of which are specifically incorporated herein byreference.) A substance, or a compound or an agent is an SV2A inhibitoreven if it does not itself bind to SV2A, as long as it causes, oraffects the ability of, another compound or agent to bind SV2A or reducesynaptic function by reducing pre-synaptic vesicle release. SV2Ainhibitors, as used herein, include pharmaceutically acceptable salts ofthe inhibitors thereof. They also include hydrates, polymorphs,prodrugs, salts, and solvates of these inhibitors.

“Antipsychotic”, “antipsychotic agent”, “antipsychotic drug”, or“antipsychotic compound” refers to (1) a typical or an atypicalantipsychotic; (2) an agent that is selected from dopaminergic agents,glutamatergic agents, NMDA receptor positive allosteric modulators,glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropicglutamate receptors (mGluRs) agonists or positive allosteric modulators(PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5positive allosteric modulators (PAMs), M1 muscarinic acetylcholinereceptor (mAChR) positive allosteric modulators (PAMs), histamine H3receptor antagonists, AMPA/kainate receptor antagonists, ampakines(CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,nNOS inhibits, neurosteroids, and neurotrophic factors; and/or (3) anagent that is useful in treating one or more signs or symptoms ofschizophrenia or bipolar disorder (in particular, mania).

“Typical antipsychotics”, as used herein, refer to conventionalantipsychotics, which produce antipsychotic effects as well as movementrelated adverse effects related to disturbances in the nigrostriataldopamine system. These extrapyramidal side effects (EPS) includeParkinsonism, akathisia, tardive dyskinesia and dystonia. SeeBaldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basisof Therapeutics 10 Edition, 2001, pp. 485-520.

“Atypical antipsychotics”, as used herein, refer to antipsychotic drugsthat produce antipsychotic effects with little or no EPS and include,but are not limited to, aripiprazole, asenapine, clozapine, iloperidone,olanzapine, lurasidone, paliperidone, quetiapine, risperidone andziprasidone. “Atypical” antipsychotics differ from conventionalantipsychotics in their pharmacological profiles. While conventionalantipsychotics are characterized principally by D₂ dopamine receptorblockade, atypical antipsychotics show antagonist effects on multiplereceptors including the 5HT_(a) and 5HT_(c) serotonin receptors andvarying degrees of receptor affinities. Atypical antipsychotic drugs arecommonly referred to as serotonin/dopamine antagonists, reflecting theinfluential hypothesis that greater affinity for the 5HT₂ receptor thanfor the D₂ receptor underlies “atypical” antipsychotic drug action or“second generation” antipsychotic drugs. However, the atypicalantipsychotics often display side effects, including, but not limitedto, weight gain, diabetes (e.g., type II diabetes mellitus),hyperlipidemia, QTc interval prolongation, myocarditis, sexual sideeffects, extrapyramidal side effects and cataract. Thus, atypicalantipsychotics do not represent a homogeneous class, given theirdifferences in the context of both alleviation of clinical symptoms andtheir potential for inducing side effects such as the ones listed above.Further, the common side effects of the atypical antipsychotics asdescribed above often limit the antipsychotic doses that can be used forthese agents.

The term “simultaneous administration,” as used herein, means that theSV2A inhibitor and the antipsychotic, or their pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs, areadministered with a time separation of no more than about 15 minutes,and in some embodiments no more than about 10 minutes. When the drugsare administered simultaneously, the SV2A inhibitor and theantipsychotic, or their salts, hydrates, solvates, polymorphs orprodrugs, may be contained in the same dosage (e.g., a unit dosage formcomprising both the SV2A inhibitor and the antipsychotic) or in discretedosages (e.g., the SV2A inhibitor or its salt, hydrate, solvate,polymorph, or prodrug is contained in one dosage form and theantipsychotic or its salt, hydrate, solvate, polymorph, or prodrug iscontained in another dosage form).

The term “sequential administration” as used herein means that the SV2Ainhibitor and the antipsychotic, or their pharmaceutically acceptablesalts, hydrates, solvates, polymorphs, are administered with a timeseparation of more than about 15 minutes, and in some embodiments morethan about one hour, or up to 12-24 hours. Either the SV2A inhibitor orthe antipsychotic may be administered first. The SV2A inhibitor and theantipsychotic, or their salts, hydrates, solvents, or polymorphs, forsequential administration may be contained in discrete dosage forms,optionally contained in the same container or package.

A “therapeutically effective amount” of a drug or agent is an amount ofa drug or an agent that, when administered to a subject will have theintended therapeutic effect, e.g. improving cognitive function in asubject in a subject suffering from a disease or disorder (e.g.,schizophrenia or bipolar disorder (in particular, mania)), preventing orslowing the progression of a disease or disorder (e.g., schizophrenia orbipolar disorder (in particular, mania)), and/or alleviating,ameliorating, or slowing the progression of one or more symptomsassociated with the disease or disorder (e.g., schizophrenia or bipolardisorder (in particular, mania)). The full therapeutic effect does notnecessarily occur by administration of one dose, and may occur onlyafter administration of a series of doses. Thus, a therapeuticallyeffective amount may be administered in one or more administrations. Theprecise effective amount needed for a subject will depend upon, forexample, the subject's size, health and age, the nature and extent ofthe cognitive impairment, and the therapeutics or combination oftherapeutics selected for administration, and the mode ofadministration. The skilled worker can readily determine the effectiveamount for a given situation by routine experimentation.

“Subtherapeutic amount” refers to an amount administered of an agent orcompound of the invention that is less than the therapeutic amount, thatis, less than the amount normally used when said agent or compound isadministered alone (i.e., individually and in the absence of othertherapeutic agents or compounds) to treat disorders, such asschizophrenia or bipolar disorder (in particular, mania).

“Analog” is used herein to refer to a compound which functionallyresembles another chemical entity, but does not share the identicalchemical structure. For example, an analog is sufficiently similar to abase or parent compound such that it can substitute for the basecompound in therapeutic applications, despite minor structuraldifferences.

“Derivative” is used herein to refer to the chemical modification of acompound. Chemical modifications of a compound can include, for example,replacement of hydrogen by an alkyl, acyl, or amino group. Many othermodifications are also possible.

The term “prodrug” is art-recognized and is intended to encompasscompounds or agents which, under physiological conditions, are convertedinto an SV2A inhibitor or an antipsychotic. A common method for making aprodrug is to select moieties which are hydrolyzed or metabolized underphysiological conditions to provide the desired compound or agent. Inother embodiments, the prodrug is converted by, for example, anenzymatic activity of the host animal to an SV2A inhibitor or anantipsychotic.

The term “aliphatic” as used herein means a straight chained or branchedalkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynylembodiments need at least two carbon atoms in the aliphatic chain.Aliphatic groups typically contains from 1 (or 2) to 12 carbons, such asfrom 1 (or 2) to 4 carbons.

The term “aryl” as used herein means a monocyclic or bicycliccarbocyclic aromatic ring system. For example, aryl as used herein canbe a C5-C10 monocyclic or C8-C12 bicyclic carbocyclic aromatic ringsystem. Phenyl is an example of a monocyclic aromatic ring system.Bicyclic aromatic ring systems include systems wherein both rings arearomatic, e.g., naphthyl, and systems wherein only one of the two ringsis aromatic, e.g., tetralin.

The term “heterocyclic” as used herein means a monocyclic or bicyclicnon-aromatic ring system having 1 to 3 heteroatom or heteroatom groupsin each ring selected from O, N, NH, S, SO, or SO₂ in a chemicallystable arrangement. For example, heterocyclic as used herein can be aC5-C10 monocyclic or C8-C12 bicyclic non-aromatic ring system having 1to 3 heteroatom or heteroatom groups in each ring selected from O, N,NH, S, SO, or SO₂ in a chemically stable arrangement. In a bicyclicnon-aromatic ring system embodiment of “heterocyclyl”, one or both ringsmay contain said heteroatom or heteroatom groups. In another bicyclic“heterocyclyl” embodiment, one of the two rings may be aromatic. In yetanother heterocyclic ring system embodiment, a non-aromatic heterocyclicring may optionally be fused to an aromatic carbocycle.

Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino,3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

The term “heteroaryl” as used herein means a monocyclic or bicyclicaromatic ring system having 1 to 3 heteroatom or heteroatom groups ineach ring selected from O, N, NH or S in a chemically stablearrangement. For example, heteroaryl as used herein can be a C5-C10monocyclic or C8-C12 bicyclic aromatic ring system having 1 to 3heteroatom or heteroatom groups in each ring selected from O, N, NH or Sin a chemically stable arrangement. In such a bicyclic aromatic ringsystem embodiment of “heteroaryl”:

-   -   both rings are aromatic; and    -   one or both rings may contain said heteroatom or heteroatom        groups.

Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g.,5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl,3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl),pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl,pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “cycloalkyl or cycloalkenyl” refers to a monocyclic or fused orbridged bicyclic carbocyclic ring system that is not aromatic. Forexample, cycloalkyl or cycloalkenyl as used herein can be a C5-C10monocyclic or fused or bridged C8-C12 bicyclic carbocyclic ring systemthat is not aromatic.

Cycloalkenyl rings have one or more units of unsaturation. Preferredcycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,norbornyl, adamantyl and decalinyl.

As used herein, the carbon atom designations may have the indicatedinteger and any intervening integer. For example, the number of carbonatoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understoodthat these designation refer to the total number of atoms in theappropriate group. For example, in a (C3-C10)-heterocyclyl the totalnumber of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6(as in morpholine), 7, 8, 9, or 10.

“Pharmaceutically acceptable salt” is used herein to refer to an agentor a compound according to the invention that is a therapeuticallyactive, non-toxic base and acid salt form of the compounds. The acidaddition salt form of a compound that occurs in its free form as a basecan be obtained by treating said free base form with an appropriate acidsuch as an inorganic acid, for example, a hydrohalic such ashydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like;or an organic acid, such as, for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclic, salicylic, p-aminosalicylic, pamoic and thelike. See, e.g., WO 01/062726.

Compounds containing acidic protons may be converted into theirtherapeutically active, non-toxic base addition salt form, e. g. metalor amine salts, by treatment with appropriate organic and inorganicbases. Appropriate base salt forms include, for example, ammonium salts,alkali and earth alkaline metal salts, e. g., lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e. g. N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.Conversely, said salt forms can be converted into the free forms bytreatment with an appropriate base or acid. Compounds and their saltscan be in the form of a solvate, which is included within the scope ofthe present invention. Such solvates include for example hydrates,alcoholates and the like. See, e.g., WO 01/062726.

As used herein, the term “hydrate” refers to a combination of water witha compound wherein the water retains its molecular state as water and iseither absorbed, adsorbed or contained within a crystal lattice of thesubstrate compound.

As used herein, the term “polymorph” refers to different crystallineforms of the same compound and other solid state molecular formsincluding pseudo-polymorphs, such as hydrates (e.g., bound water presentin the crystalline structure) and solvates (e.g., bound solvents otherthan water) of the same compound. Different crystalline polymorphs havedifferent crystal structures due to a different packing of the moleculesin the lattice. This results in a different crystal symmetry and/or unitcell parameters which directly influences its physical properties suchthe X-ray diffraction characteristics of crystals or powders. Adifferent polymorph, for example, will in general diffract at adifferent set of angles and will give different values for theintensities. Therefore X-ray powder diffraction can be used to identifydifferent polymorphs, or a solid form that comprises more than onepolymorph, in a reproducible and reliable way. Crystalline polymorphicforms are of interest to the pharmaceutical industry and especially tothose involved in the development of suitable dosage forms. If thepolymorphic form is not held constant during clinical or stabilitystudies, the exact dosage form used or studied may not be comparablefrom one lot to another. It is also desirable to have processes forproducing a compound with the selected polymorphic form in high puritywhen the compound is used in clinical studies or commercial productssince Impurities present may produce undesired toxicological effects.Certain polymorphic forms may exhibit enhanced thermodynamic stabilityor may be more readily manufactured in high purity in large quantities,and thus are more suitable for inclusion in pharmaceutical formulations.Certain polymorphs may display other advantageous physical propertiessuch as lack of hygroscopic tendencies, improved solubility, andenhanced rates of dissolution due to different lattice energies.

Many of the compounds useful in the methods and compositions of thisinvention have at least one stereogenic center in their structure. Thisstereogenic center may be present in a R or a S configuration, said Rand S notation is used in correspondence with the rules described inPure Appl. Chem. (1976), 45, 11-30. The invention also relates to allstereoisomeric forms such as enantiomeric and diastereoisomeric forms ofthe compounds or mixtures thereof (including all possible mixtures ofstereoisomers). See, e.g., WO 01/062726.

Furthermore, certain compounds which contain alkenyl groups may exist asZ (zusammen) or E (entgegen) isomers. In each instance, the inventionincludes both mixture and separate individual isomers. Multiplesubstituents on a piperidinyl or the azepanyl ring can also stand ineither cis or trans relationship to each other with respect to the planeof the piperidinyl or the azepanyl ring. Some of the compounds may alsoexist in tautomeric forms. Such forms, although not explicitly indicatedin the formulae described herein, are intended to be included within thescope of the present invention. With respect to the methods andcompositions of the present invention, reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof unless the particular isomeric formis referred to specifically. See, e.g., WO 01/062726.

DESCRIPTION OF METHODS OF THE INVENTION

The methods of this invention comprise administration of an SV2Ainhibitor or a pharmaceutically acceptable salt thereof in combinationwith administration of an antipsychotic or a pharmaceutically acceptablesalt thereof. The agents or compounds of the SV2A inhibitor or theantipsychotic and their pharmaceutically acceptable salts also includehydrates, solvates, polymorphs, and prodrugs of those agents, compounds,and salts.

Methods of Assessing Cognitive Impairment

Animal models serve as an important resource for developing andevaluating treatments for CNS disorders with cognitive impairment.Features that characterize cognitive impairment in animal modelstypically extend to cognitive impairment in humans. Efficacy in suchanimal models is, thus, expected to be predictive of efficacy in humans.The extent of cognitive impairment in an animal model for a CNSdisorder, and the efficacy of a method of treatment for said CNSdisorder may be tested and confirmed with the use of a variety ofcognitive tests.

A Radial Arm Maze (RAM) behavioral task is one example of a cognitivetest, specifically testing spacial memory (Chappell et al.Neuropharmacology 37: 481-487, 1998). The RAM apparatus consists of,e.g., eight equidistantly spaced arms. A maze arm projects from eachfacet of a center platform. A food well is located at the distal end ofeach arm. Food is used as a reward. Blocks can be positioned to prevententry to any arm. Numerous extra maze cues surrounding the apparatus mayalso be provided. After habituation and training phases, spatial memoryof the subjects may be tested in the RAM under control or testcompound-treated conditions. As a part of the test, subjects arepretreated before trials with a vehicle control or one of a range ofdosages of the test compound. At the beginning of each trial, a subsetof the arms of the eight-arm maze is blocked. Subjects are allowed toobtain food on the unblocked arms to which access is permitted duringthis initial “information phase” of the trial. Subjects are then removedfrom the maze for a delay period, e.g., a 60 second delay, a 15 minutedelay, a one-hour delay, a two-hour delay, a six hour delay, a 24 hourdelay, or longer) between the information phase and the subsequent“retention test,” during which the barriers on the maze are removed,thus allowing access to all eight arms. After the delay period, subjectsare placed back onto the center platform (with the barriers to thepreviously blocked arms removed) and allowed to obtain the remainingfood rewards during this retention test phase of the trial. The identityand configuration of the blocked arms vary across trials. The number of“errors” the subjects make during the retention test phase is tracked.An error occurs in the trial if the subjects entered an arm from whichfood had already been retrieved in the pre-delay component of the trial,or if it re-visits an arm in the post-delay session that had alreadybeen visited. A fewer number of errors would indicate better spatialmemory. The number of errors made by the test subject, under varioustest compound treatment regimes, can then be compared for efficacy ofthe test compound in treating CNS disorders with cognitive impairment.

Another cognitive test that may be used to assess the effects of a testcompound on the cognitive impairment of a CNS disorder model animal isthe Morris water maze. A water maze is a pool surrounded with a novelset of patterns relative to the maze. The training protocol for thewater maze may be based on a modified water maze task that has beenshown to be hippocampal-dependent (de Hoz et al., Eur. J. Neurosci.,22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999). Thesubject is trained to locate a submerged escape platform hiddenunderneath the surface of the pool. During the training trial, a subjectis released in the maze (pool) from random starting positions around theperimeter of the pool. The starting position varies from trial to trial.If the subject does not locate the escape platform within a set time,the experimenter guides and places the subject on the platform to“teach” the location of the platform. After a delay period following thelast training trial, a retention test in the absence of the escapeplatform is given to assess spatial memory. The subject's level ofpreference for the location of the (now absent) escape platform, asmeasured by, e.g., the time spent in that location or the number ofcrossings of that location made by the mouse, indicates better spatialmemory, i.e., treatment of cognitive impairment. The preference for thelocation of the escape platform under different treatment conditions,can then be compared for efficacy of the test compound in treating CNSdisorders with cognitive impairment.

There are various tests known in the art for assessing cognitivefunction in humans, for example and without limitation, the clinicalglobal impression of change scale (CIBIC-plus scale); the Mini MentalState Exam (MMSE); the Neuropsychiatric Inventory (NPI); the ClinicalDementia Rating Scale (CDR); the Cambridge Neuropsychological TestAutomated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric(SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974);the Verbal Paired Associates subtest; the Logical Memory subtest; theVisual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R)(Wechsler, 1997); the Benton Visual Retention Test, or MATRICS consensusneuropsychological test battery which includes tests of working memory,speed of processing, attention, verbal learning, visual learning,reasoning and problem solving and social cognition. See Folstein et al.,J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger etal., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002and Masur et al., 1994. Also see Buchanan, R. W., Keefe, R. S. E.,Umbricht, D., Green, M. F., Laughren, T., and Marder, S. R. (2011) TheFDA-NIMH-MATRICS guidelines for clinical trial design ofcognitive-enhancing drugs: what do we know 5 years later? Schizophr.Bull. 37, 1209-1217. Another example of a cognitive test in humans isthe explicit 3-alternative forced choice task. In this test, subjectsare presented with color photographs of common objects consisting of amix of three types of image pairs: similar pairs, identical pairs andunrelated foils. The second of the pair of similar objects is referredto as the “lure”. These image pairs are fully randomized and presentedindividually as a series of images. Subjects are instructed to make ajudgment as to whether the objects seen are new, old or similar. A“similar” response to the presentation of a lure stimulus indicatessuccessful memory retrieval by the subject. By contrast, calling thelure stimulus “old” or “new” indicates that correct memory retrieval didnot occur.

Schizophrenia

This invention provides methods and compositions for treatingschizophrenia or bipolar disorder (in particular, mania) using an SV2Ainhibitor or a pharmaceutically acceptable salt thereof in combinationwith an antipsychotic or a pharmaceutically acceptable salt thereof. Incertain embodiments, treatment comprises preventing or slowing theprogression of schizophrenia or bipolar disorder (in particular, mania).Schizophrenia is characterized by a wide spectrum of psychopathology,including positive symptoms such as aberrant or distorted mentalrepresentations (e.g., hallucinations, delusions), negative symptomscharacterized by diminution of motivation and adaptive goal-directedaction (e.g., anhedonia, affective flattening, avolition), and cognitiveimpairment. In certain embodiments, treatment comprises alleviation,amelioration or slowing the progression of one or more positive and/ornegative symptoms, as well as cognitive impairment, associated withschizophrenia. Further, there are a number of other psychiatric diseasessuch as schizotypical and schizoaffective disorder, other acute- andchronic psychoses and bipolar disorder (in particular, mania), whichhave an overlapping symptomatology with schizophrenia. In someembodiments, treatment comprises alleviation, amelioration or slowingthe progression of one or more symptoms, as well as cognitiveimpairment, associated with bipolar disorder (in particular, mania). Themethods and compositions may be used for human patients in clinicalapplications in treating schizophrenia or bipolar disorder (inparticular, mania). The dose of the composition and dosage interval forthe method is, as described herein, one that is safe and efficacious inthose applications.

Cognitive impairments are associated with schizophrenia. They precedethe onset of psychosis and are present in non-affected relatives. Thecognitive impairments associated with schizophrenia constitute a goodpredictor for functional outcome and are a core feature of the disorder.Cognitive features in schizophrenia reflect dysfunction in frontalcortical and hippocampal circuits. Patients with schizophrenia alsopresent hippocampal pathologies such as reductions in hippocampalvolume, reductions in neuronal size and dysfunctional hyperactivity. Animbalance in excitation and inhibition in these brain regions has alsobeen documented in schizophrenic patients suggesting that drugstargeting inhibitory mechanisms could be therapeutic. See, e.g.,Guidotti et al., Psychopharmacology 180: 191-205, 2005; Zierhut, Psych.Res. Neuroimag. 183:187-194, 2010; Wood et al., NeuroImage 52:62-63,2010; Vinkers et al., Expert Opin. Investig. Drugs 19:1217-1233, 2009;Young et al., Pharmacol. Ther. 122:150-202, 2009.

Animal models serve as an important resource for developing andevaluating treatments for schizophrenia. Features that characterizeschizophrenia in animal models typically extend to schizophrenia inhumans. Thus, efficacy in such animal models is expected to bepredictive of efficacy in humans. Various animal models of schizophreniaare known in the art.

One animal model of schizophrenia is protracted treatment withmethionine. Methionine-treated mice exhibit deficient expression ofGAD67 in frontal cortex and hippocampus, similar to those reported inthe brain of postmortem schizophrenia patients. They also exhibitprepulse inhibition of startle and social interaction deficits(Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal modelof schizophrenia is methylaoxymethanol acetate (MAM)-treatment in rats.Pregnant female rats are administered MAM (20 mg/kg, intraperitoneal) ongestational day 17. MAM-treatment recapitulate a pathodevelopmentalprocess to schizophrenia-like phenotypes in the offspring, includinganatomical changes, behavioral deficits and altered neuronal informationprocessing. More specifically, MAM-treated rats display a decreaseddensity of parvalbumin-positive GABAergic interneurons in portions ofthe prefrontal cortex and hippocampus. In behavioral tests, MAM-treatedrats display reduced latent inhibition. Latent inhibition is abehavioral phenomenon where there is reduced learning about a stimulusto which there has been prior exposure with any consequence. Thistendency to disregard previously benign stimuli, and reduce theformation of association with such stimuli is believed to preventsensory overload. Low latent inhibition is indicative of psychosis.Latent inhibition may be tested in rats in the following manner. Ratsare divided into two groups. One group is pre-exposed to a tone overmultiple trials. The other group has no tone presentation.

Both groups are then exposed to an auditory fear conditioning procedure,in which the same tone is presented concurrently with a noxiousstimulus, e.g. an electric shock to the foot. Subsequently, both groupsare presented with the tone, and the rats' change in locomotor activityduring tone presentation is monitored. After the fear conditioning therats respond to the tone presentation by strongly reducing locomotoractivity. However, the group that has been exposed to the tone beforethe conditioning period displays robust latent inhibition: thesuppression of locomotor activity in response to tone presentation isreduced. MAM-treated rats, by contrast show impaired latent inhibition.That is, exposure to the tone previous to the fear conditioningprocedure has no significant effect in suppressing the fearconditioning. (see Lodge et al., J. Neurosci., 29:2344-2354, 2009) Suchanimal models of schizophrenia may be used to assay the effectiveness ofthe methods and compositions of the invention in treating schizophreniaor bipolar disorder (in particular, mania).

MAM-treated rats display a significantly enhanced locomotor response (oraberrant locomotor activity) to low dose D-amphetamine administration.The MAM-treated rats also display a significantly greater number ofspontaneously firing ventral tegmental dopamine (DA) neurons. Theseresults are believed to be a consequence of excessive hippocampalactivity because in MAM-treated rats, the ventral hippocampus (vHipp)inactivation (e.g., by intra-vHipp administration of a sodium channelblocker, tetrodotoxin (TTX), to MAM rats) completely reversed theelevated DA neuron population activity and also normalized the augmentedamphetamine-induced locomotor behavior. The correlation of hippocampaldysfunction and the hyper-responsivity of the DA system is believed tounderlie the augmented response to amphetamine in MAM-treated animalsand psychosis in schizophrenia patients. See Lodge D. J. et al.Neurobiology of Disease (2007), 27(42), 11424-11430. The use ofMAM-treated rats in the above study may be suitable for use to assay theeffectiveness of the methods and compositions of the present inventionin treating schizophrenia or bipolar disorder (in particular, mania).For example, the methods and compositions of this invention maybeevaluated, using MAM-treated animals, for their effects on the centralhippocampus (vHipp) regulation, on the elevated DA neuron populationactivity and on the hyperactive locomotor response to amphetamine in theMAM-treated animals.

In MAM-treated rats, hippocampal (HPC) dysfunction leads to dopaminesystem hyperactivity. A benzodiazepine-positive allosteric modulator(PAM), selective for the α5 subunit of the GABA_(A) receptor,SH-053-2′F—R—CH₃, is tested for its effects on the output of thehippocampal (HPC). The effect of SH-053-2′F—R—CH₃ on the hyperactivelocomotor response to amphetamine in MAM-treated animals is alsoexamined. The α5GABAAR PAM reduces the number of spontaneously active DAneurons in the ventral tegmental area (VTA) of MAM rats to levelsobserved in saline-treated rats (control group), both when administeredsystemically and when directly infused into the ventral HPC. Moreover,HPC neurons in both saline-treated and MAM-treated animals showdiminished cortical-evoked responses following the α5GABAAR PAMtreatment. In addition, the increased locomotor response to amphetamineobserved in MAM-treated rats is reduced following the α5GABA_(A)R PAMtreatment. See Gill K. M et al. Neuropsychopharmacology (2011), 1-9. Theuse of MAM-treated rats in the above study may be suitable for use inthe present invention to assay the effectiveness of the methods andcompositions of the invention in treating schizophrenia or bipolardisorder (in particular, mania). For example, the methods andcompositions of this invention maybe evaluated, using MAM-treatedanimals, for their effects on the output of the hippocampal (HPC) and onthe hyperactive locomotor response to amphetamine in the MAM-treatedanimals.

Administration of MAM to pregnant rats on embryonic day 15 (E15)severely impairs spatial memory or the ability to learn the spatiallocation of four items on an eight-arm radial maze in the offspring. Inaddition, embryonic day 17 (E17) MAM-treated rats are able to reach thelevel of performance of control rats at the initial stages of training,but are unable to process and retrieve spatial information when a 30-mindelay is interposed, indicating a significant impairment in workingmemory. See Gourevitch R. et al. (2004). Behav. Pharmacol, 15, 287-292.Such animal models of schizophrenia may be used to assay theeffectiveness of the methods and compositions of the invention intreating schizophrenia or bipolar disorder (in particular, mania).

Apomorphine-induced climbing (AIC) and stereotype (AIS) in mice isanother animal model useful in this invention. Agents are administeredto mice at a desired dose level (e.g., via intraperitonealadministration). Subsequently, e.g., thirty minutes later, experimentalmice are challenges with apomorphine (e.g., with 1 mg/kg sc). Fiveminutes after the apomorphine injection, the sniffing-licking-gnawingsyndrome (stereotyped behavior) and climbing behavior induced byapomorphine are scored and recorded for each animal. Readings can berepeated every 5 min during a 30-min test session. Scores for eachanimal are totaled over the 30-min test session for each syndrome(stereotyped behavior and climbing). If an effect reached at least of50% inhibition, and ID₅₀ value (95% confidence interval) is calculatedusing a nonlinear least squares calculation with inverse prediction.Mean climbing and stereotype scores can be expressed as a percent ofcontrol values observed in vehible treated (e.g., saline-treated) micethat receive apomorphine. See Grauer S. M. et al. Psychopharmacology(2009) 204, 37-48. This mice model may be used to assay theeffectiveness of the methods and compositions of the invention intreating schizophrenia or bipolar disorder (in particular, mania).

The efficacy of the methods and compositions of this invention intreating schizophrenia may also be assessed in animal models ofschizophrenia or bipolar disorder (in particular, mania), as well ashuman subjects with schizophrenia, using a variety of cognitive testsknown in the art, as discussed above.

SV2A Inhibitors

“Synaptic vesicle protein-2 (SV2)” is a family of synaptic vesicleproteins, which consists of three members, designated SV2A, SV2B, andSV2C. SV2A is the most widely distributed family member, being expressedubiquitously in the brain. The proteins are integral membrane proteinsand have a low-level homology (20-30%) to the twelve transmembranefamily of bacterial and fungal transporter proteins that transportsugar, citrate, and xenobiotics (Bajjalieh et al., Science. 257:1271-1273. (1992)). SV2 family proteins are present in the brain andendocrine cells, and further are present in all synaptic and endocrinevesicles. SV2 proteins are reported to play a role in normal synapticfunction, and functions in a maturation step of primed vesicles thatconverts the vesicles into a Ca(²⁺)— and synaptotagmin-responsive state(Sudhof et al., 2009). Functionally, SV2 proteins are reported toenhance synaptic currents and increase the probability of transmitterrelease by maintaining the size of the readily releasable pool ofvesicles (Custer et al., 2006).

“SV2A inhibitor” refers to any agent, substance or compound that bindsto SV2A and reduces synaptic function by reducing pre-synaptic vesiclerelease (See, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al.2004; Gillard et al. 2006; Custer et al., 2006; Smedt et al., 2007; Yanget al., 2007; Meehan, “Levetiracetam has an activity-dependent effect oninhibitory transmission,” Epilepsia, 2012 Jan. 31; and Example 8 of WO2001/62726, all of which are specifically incorporated herein byreference.) A substance, or a compound or an agent is an SV2A inhibitoreven if it does not itself bind to SV2A, as long as it causes, oraffects the ability of, another compound or agent to bind SV2A or reducesynaptic function by reducing pre-synaptic vesicle release. SV2Ainhibitors, as used herein, include pharmaceutically acceptable salts ofthe inhibitors thereof. They also include hydrates, polymorphs,prodrugs, salts, and solvates of these inhibitors.

Among the SV2A inhibitors or pharmaceutically acceptable salts,hydrates, solvates, polymorphs and prodrugs thereof that are useful inthe methods and compositions of this invention are those disclosed, forexample, U.S. patent application Ser. No. 12/580,464 (Pub. No.US-2010-0099735), U.S. patent application Ser. No. 13/287,531 (Pub. No.US-2012-0046336), U.S. patent application Ser. No. 13/370,253 (Pub. No.US-2012-0214859), International Patent Application PCT/US2009/005647(Pub. No. WO2010/044878), International Patent ApplicationPCT/US12/24556 (Pub. No. WO2012/109491), U.S. Patent ProvisionalApplication 61/105,847, 61/152,631, 61/175,536, and 61/441,251. However,any SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof may be used in the methods andcompositions of the invention. In some embodiments, the SV2A inhibitoris selected from the group of SV2A inhibitors referred to inInternational Patent Applications WO2010/144712; WO2010/002869;WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692;WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726; U.S. Pat.Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692 or theirpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs. Other SV2A inhibitors may also be used in this invention.Applicants also refer to methods of preparing these compounds found inthe documents cited above. Other synthetic methods may also be used.These methods are well known to those skilled in the art.

In some embodiments of this invention, the SV2A inhibitor is selectedfrom the group consisting of levetiracetam, brivaracetam, andseletracetam or derivatives or analogs or pharmaceutically acceptablesalts, solvates, hydrates, polymorphs, or prodrugs thereof.

In some embodiments of this invention, the SV2A inhibitor islevetiracetam or salts, solvates, hydrates, polymorphs or prodrugsthereof. Levetiracetam refers to the International Union of Pure andApplied Chemistry (IUPAC) name of the compound(2S)-2-(2-oxopyrrolidin-1-yl) butanamide). Levetiracetam is a widelyused antiepileptic drug. Levetiracetam binds to a specific site in theCNS: the synaptic vesicle protein 2A (SV2A) (See. e.g., Noyer et al.1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006) and hasfurther been shown to directly inhibit synaptic activity andneurotransmission by inhibiting presynaptic neurotransmitter release(Yang et al., 2007).

Among the SV2A inhibitors useful for the methods and compositions ofthis invention are the following:

i) International Patent Application WO 2001/062726:

A compound having the formula I or a pharmaceutically acceptable saltthereof,

wherein X is —CA¹NR⁵R⁶ or —CA¹OR⁷ or —CA¹-R⁸ or CN;

A¹ and A² are independently oxygen, sulfur or —NR⁹;

R¹ is hydrogen, alkyl, aryl or —CH₂—R^(1a) wherein R^(1a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

R², R³ and R⁴ are the same or different and each is independentlyhydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido,carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl,ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative,amino derivative, acyl derivative, sulfonyl derivative or sulfinylderivative;

R^(2a), R^(3a) and R^(4a) are the same or different and each isindependently hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;

R⁵, R⁶, R⁷ and R⁹ are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or athio derivative;

with the provisos that at least one of as R², R³, R⁴, R^(2a), R^(3a) andR^(4a) is other than hydrogen; and that when the compound is a mixtureof all possible isomers, X is —CONR⁵R⁶, A² is oxygen and R¹ is hydrogen,methyl, ethyl or propyl then substitution on the pyrollidine ring isother than mono-, di-, or tri-methyl or mono-ethyl; and that when R¹,R², R⁴, R^(2a), R^(3a) and R^(4a) are each hydrogen, A² is oxygen and Xis CONR⁵R⁶ then R³ is different from carboxy, ester, amido, substitutedoxo-pyrrolidine, hydroxy, oxy derivative, amino, amino derivatives,methyl, naphthyl, phenyl optionally substituted by oxy derivatives or inthe para position by an halogen atom.

In the definitions set forth below, unless otherwise stated, R¹¹ and R¹²are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein is defined as including —O—R¹¹groups wherein R¹¹ is as defined above except for “oxy derivative”.Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy,oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy,arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy,allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy,2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative” as used herein, is defined as including—S—R¹¹ groups wherein R¹¹ is as defined above except for “thioderivative”. Non-limiting examples are alkylthio, alkenylthio,alkynylthio and arylthio.

The term “amino derivative” as used herein, is defined as including—NHR¹¹ or —NR¹¹R¹² groups wherein R¹¹ and R¹² are as defined above.Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- andarylamino or mixed amino.

The term “acyl derivative” as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R¹¹—CO—, wherein R¹¹ is as defined above and may also behydrogen. Non-limiting examples are formyl, acetyl, propionyl,isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl,crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl,4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

The term “sulfonyl derivative” as used herein, is defined as including agroup of the formula —SO₂—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfonyl derivative”. Non-limiting examples are alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative” as used herein, is defined as including agroup of the formula —SO—R¹¹, wherein R¹¹ is as defined above except for“sulfinyl derivative”. Non-limiting examples are alkylsulfinyl,alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and containing 1-20 carbon atoms,preferably 1-6 carbon atoms for non-cyclic alkyl and 3-6 carbon atomsfor cycloalkyl (in these two preferred cases, unless otherwisespecified, “lower alkyl”). Alkyl moieties may optionally be substitutedby 1 to 5 substituents independently selected from the group consistingof halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl,acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy,ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thioderivative, oxyester, oxyamido, heterocycle, vinyl, C1-5-alkoxy,C6-10-aryloxy and C6-10-aryl.

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, and 2,2,2-trimethylethyl each optionally substituted by atleast one substituent selected from the group consisting of halogen,hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl,trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

The term “alkenyl” as used herein, is defined as including both branchedand unbranched, unsaturated hydrocarbon radicals having at least onedouble bond such as ethenyl (=vinyl), 1-methyl-1-ethenyl,2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl,2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl,3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, and the like and beingoptionally substituted by at least one substituent selected from thegroup consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryland heterocycle such as mono- and di-halo vinyl where halo is fluoro,chloro or bromo.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl and heterocycle, such as haloethynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e.g., “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl” as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of 1-3 rings andcontaining 6-30 carbon atoms by removal of one hydrogen, such as phenyland naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, hydroxy, thiol, amino, nitro,cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester,ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl,alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, C1-6-alkoxy,C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. Aryl radicals are preferablymonocyclic containing 6-10 carbon atoms. Preferred aryl groups arephenyl and naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl and phenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO₂.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “azido”, as used herein, represents a group of the formula —N₃.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO₃H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

The term “ester”, as used herein is defined as including a group offormula —COO—R¹¹ wherein R¹¹ is as defined above except oxy derivative,thio derivative or amino derivative.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH₂ or—CONHR¹¹ or —CONR¹¹R¹² wherein R¹¹ and R¹² are as defined above.

The term “heterocycle”, as used herein is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Non-limitingexamples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl,isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thieno (2,3-b) furanyl, furopyranyl, benzofuranyl,benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl, benzothiazolyl, orbenzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl,acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl,isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, and pyrazolopyrimidinyl optionally substituted byalkyl or as described above for the alkyl groups. Non-limiting examplesof non aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino,morpholinyl, 1-oxaspiro(4.5) dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl,sugar moieties (i.e. glucose, pentose, hexose, ribose, fructose, whichmay also be substituted) or the same which can optionally be substitutedwith any suitable group, including but not limited to one or moremoieties selected from lower alkyl, or other groups as described abovefor the alkyl groups. The term “heterocycle” also includes bicyclic,tricyclic and tetracyclic, Spiro groups in which any of the aboveheterocyclic rings is fused to one or two rings independently selectedfrom an aryl ring, a cyclohexane ring, a cyclohexene ring, acyclopentane ring, a cyclopentene ring or another monocyclicheterocyclic ring or where a monocyclic heterocyclic group is bridged byan alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl,7-oxabicyclo(2.2.1) heptanyl, 8-azabicyclo(3.2.1)octanyl.

In the above definitions it is to be understood that when a substituentsuch as R², R³, R⁴, R^(2a), R^(3a), R^(4a), R⁵, R⁶, R⁷, R⁸ is attachedto the rest of the molecule via a heteroatom or a carbonyl, a straight-or branched chain, C1-12-, preferably C1-4-alkylene or C2-12, preferablyC2-4-alkenylene or -alkynylene bridge may optionally be interposedbetween the heteroatom or the carbonyl and the point of attachment tothe rest of the molecule.

Preferred examples of X are —COO R⁷ or —CONR⁵R⁶, wherein R⁵, R⁶ and R⁷are preferably hydrogen, C1-4-alkyl, phenyl or alkylphenyl.

Preferably X is carboxy or —CONR⁵R⁶, wherein R⁵ and R⁶ are preferablyhydrogen, C1-4-alkyl, phenyl or alkylphenyl, especially —CONH₂.

Preferably A¹ and A² are each oxygen.

Preferably R¹ is hydrogen, alkyl, especially C1-12 alkyl, particularlylower alkyl or aryl especially phenyl.

Examples of preferred R¹ groups are methyl, ethyl, propyl, isopropyl,butyl, iso- or ter-butyl, 2,2,2-trimethylethyl each optionally attachedvia a methylene bridge or the same substituted by at least one halogenatom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

R¹ as ethyl is especially preferred.

Preferably R² and R^(2a) are independently hydrogen, halogen or alkyl,especially lower alkyl.

Examples of preferred R² and R^(2a) groups are independently hydrogen,halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least one halogenatom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

Especially at least one and most preferably both of R² and R^(2a) arehydrogen.

Preferably R^(3a), R⁴ and R^(4a) are independently hydrogen, alkyl,especially methyl or ethyl or aryl especially phenyl or aralkyl,especially benzyl.

Examples of preferred R^(3a), R⁴ and R^(4a) groups are independentlyhydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least onehalogen atom such as trifluoromethyl, trichloromethyl,2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

Especially at least one and most preferably both of R⁴ and R^(4a) arehydrogen.

R^(3a) is particularly hydrogen or alkyl, especially lower alkyl and ismost preferably hydrogen.

Preferably R³ is hydrogen, C1-12-alkyl, especially C1-6-alkyl, eachoptionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ringeither directly or via a thio, sulfinyl, sulfonyl, carbonyl oroxycarbonyl group and optionally, a C1-4-alkylene bridge, particularlymethylene; C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyleach optionally substituted by one or more halogens; azido; cyano;amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyleach optionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl and phenyl and attached to the ring either directlyor via a carbonyl group or a C1-4-alkylene bridge, particularlymethylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl eachoptionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio, amino,azido, phenyl and nitro and each attached to the ring either directly orvia an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group andoptionally additionally a C1-4-alkylene bridge, particularly methylene.

Also, preferably, R³ is C1-6-alkyl optionally substituted by one or moresubstituents selected from halogen, thiocyanato, azido, alkoxy,alkylthio, phenylsulfonyl; nitrooxy; C2-3-alkenyl or -alkynyl eachoptionally substituted by one or more halogens or by acetyl; tetrazolyl,pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyleach optionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, amino, azido, phenyland nitro and each attached to the ring either directly or via asulfonyloxy and optionally additionally a C1-4-alkylene bridge,particularly methylene.

Other examples of preferred R³ groups are hydrogen, halogen or methyl,ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethylor the same substituted by at least one halogen atom such astrifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

R³ is especially C1-4-alkyl optionally substituted by one or moresubstituents selected from halogen, thiocyanato or azido; C2-5-alkenylor -alkynyl, each optionally substituted by one or more halogens;thienyl; or phenyl optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl, C1-6 haloalkyl or azido.

Further examples of preferred R³ groups are C1-6 alkyl and C2-6haloalkenyl.

Preferably R⁵ and R⁶ are independently hydrogen, methyl, ethyl, propyl,isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, especiallyhydrogen or methyl.

Especially at least one and most preferably both of R⁵ and R⁶ arehydrogen.

Preferably R⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isoor tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl orthe same substituted by at least one halogen atom such astrifluoromethyl, chlorophenyl.

Preferably R⁷ is hydrogen, methyl or ethyl especially hydrogen.

Preferably R⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the samesubstituted by at least one halogen atom such as trifluoromethyl,chlorobenzyl.

Preferably R⁸ is hydrogen or methyl.

Combinations of one or more of these preferred compound groups areespecially preferred.

A particular group of compounds of formula I (Compounds 1A) comprisesthose wherein,

A² is oxygen;

X is —CONR⁵R⁶ or —COOR⁷ or —CO—R⁸ or CN;

R¹ is hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R², R³, R⁴, are the same or different and each is independently hydrogenor halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, a sulfonylderivative, a sulfinyl derivative, an amino derivative, carboxy, ester,ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, a thioderivative, alkyl, alkoxy, oxyester, oxyamido, aryl, an oxy derivative,heterocycle, vinyl and R³ may additionally represent C2-5 alkenyl, C2-5alkynyl or azido each optionally substituted by one or more halogen,cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl; orphenylsulfonyloxy whereby any phenyl moiety may be substituted by one ormore halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

R^(2a), R^(3a) and R^(4a) are hydrogen;

R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen,hydroxy, alkyl, aryl, heterocycle or oxy derivative; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle,alkylthio or thio derivative.

Within these Compounds 1A, R¹ is preferably methyl, ethyl, propyl,isopropyl, butyl, or isobutyl; most preferably methyl, ethyl orn-propyl.

R² and R⁴ are preferably independently hydrogen or halogen or methyl,ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably, areeach hydrogen.

R³ is preferably C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl,azido, each optionally substituted by one or more halogen, cyano,thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl; phenyl;phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl,pyrrole, pyridine, whereby any phenyl moiety may be substituted by oneor more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

X is preferably —COOH or —COOMe or —COOEt or —CONH₂; most preferably—CONH₂.

A further particular group of compounds of formula I (Compounds 1B)comprises those wherein,

X is —CA¹NH₂, —CA¹NHCH₃ or —CA¹N (CH₃)₂;

R¹ is alkyl or phenyl;

R³ is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl,amido, aryl, heterocycle; or

R³ is CH₂R¹⁰ wherein R¹⁰ is hydrogen, cycloalkyl, oxyester,oxyalkylsulfonyl, oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl,nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio,alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy ortrifluoroethyl;

R^(3a) is hydrogen, alkyl or aryl (especially with the proviso that whenR^(3a) is hydrogen, R³ other than methyl);

or R³R^(3a) form a cycloalkyl;

and R², R^(2a), R⁴ and R^(4a) are each hydrogen.

Within the compounds of formula I,

R¹ is preferably alkyl especially C1-12- more particularly C1-6-alkyland is most preferably ethyl;

R², R^(2a), R^(3a) and R^(4a) are preferably hydrogen;

R³ is preferably selected from hydrogen; C1-12-alkyl, especiallyC1-6-alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato or alkoxy andattached to the ring either directly or via a thio, sulfinyl, sulfonyl,carbonyl or oxycarbonyl group and optionally additionally aC1-4-alkylene bridge, particularly methylene; C2-6-alkenyl or -alkynyl,especially C2-3-alkenyl or -alkynyl, each optionally substituted by oneor more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienylor piperazinyl each optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl and phenyl and attached to the ringeither directly or via a carbonyl group or a C1-4-alkylene bridge,particularly methylene; naphthyl; or phenyl, phenylalkyl orphenylalkenyl each optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy,C1-6-alkylthio, amino, azido, phenyl and nitro and each attached to thering either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl orcarbonyloxy group and optionally additionally a C1-4-alkylene bridge,particularly methylene;

R^(3a) is preferably hydrogen or C1-4-alkyl;

R⁴ and R^(4a) are preferably, independently hydrogen, C1-4-alkyl, phenylor benzyl.

A further group of compounds of formula I (Compounds 1 C) comprisesthose in racemic form wherein, when X is —CONR⁵R⁶ and R¹ is hydrogen,methyl, ethyl or propyl, then substitution on the pyrrolidine ring isother than mono-, di-, or tri-methyl or mono-ethyl.

A further group of compound of formula I (Compounds 1D) comprises thosein racemic form wherein, when X is —CONR⁵R⁶ and R¹ is hydrogen orC1-6-alkyl, C2-6-alkenyl or -alkynyl or cycloalkyl, each unsubstituted,then substitution in the ring is other than by alkyl, alkenyl oralkynyl, each unsubstituted.

A further particular group of compounds of formula I (Compounds IE)comprises those wherein,

X is —CA¹NH₂;

R¹ is H;

R³ is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5halogen atoms, n-propyl optionally substituted by 1 to 5 halogen atoms,vinyl optionally substituted by one or two methyl, and/or 1 to 3 halogenatoms, acetylene optionally substituted by C1-4-alkyl, phenyl orhalogen;

R^(3a) is hydrogen or halogen, preferably fluorine;

-   -   and R², R^(2a), R⁴ and R^(4a) are each hydrogen;    -   as their racemates or in enantiomerically enriched form,        preferably the pure enantiomers.

A further particular group of compounds of formula I (Compounds 1F)comprises those wherein,

X is —CANH₂;

R¹ is H;

R³ is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted byazido, oxynitro, 1 to 6 halogen atoms;

R^(3a) is hydrogen or halogen, preferably fluorine;

and R², R^(2a), R⁴ and R^(4a) are each hydrogen; as their racemates orin enantiomerically enriched form, preferably the pure enantiomers.

In all the above mentioned scopes when the carbon atom to which R¹ isattached is asymmetric it is preferably in the “S”-configuration.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[4-(bromomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-(2-oxo-4-phenyl-1-pyrrplidinyl)butanamide;-   (2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl    4-methylbenzenesulfonate;-   (2S)-2-[(4R)-4-(azidomethyl)-2-oxopyrrolidinyl]butanamide;-   2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl    nitrate;-   (2S)-2-[2-oxo-4-(1H-tetraazol-1-ylmethyl)-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide;-   2-{2-oxo-4-[(phenylsulfonyl)methyl]-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(2,2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[(4S)-4-(2,2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(2-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-vinylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;-   2-[4-(2-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[2-oxo-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-[1, l′-biphenyl]-4-yl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-{4-[(methylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxo-1-pyrrolidinyl]pentanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]-N-methylbutanamide;-   (2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(2,2-difluorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2,2-difluoroethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide;-   2-{4-[(Z)-2-fluoroethenyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(2-methyl-1-propenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-butyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-isobutyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(4-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-{2-oxo-4-[2-(trifluoromethyl)phenyl]-1-pyrrolidinyl}butanamide;-   2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(2-phenylethyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-{4-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2-furyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3,5-dibromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-ethynyl-2-oxo-1-pyrrolidinyl) butanamide;-   2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl}butanamide;-   (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-pyrrolidinyl]butanamide;-   2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(1H-pyrrol-1-yl)-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-[4-(2-iodopropyl)-2-oxo-1-pyrrolidinyl}butanamide;-   (2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(2-bromo-1H-pyrrol-1-yl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   (2R)-2-[4-(2,2-dichlorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[(4S)-4-(2,2-difluoropropyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)pentanamide;-   3-cyclopropyl-2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4-yl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)-4-pentenamide;-   (2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

including all isomeric forms and mixtures thereof or a pharmaceuticallyacceptable salt thereof.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide.

ii) International Patent Application WO 2002/094787:

wherein n represents 0 or 1 whereby R¹ is not existent when n=0 and R¹is existent when n=1;

A¹ represents an oxygen or a sulfur atom;

X is —CONR⁷R⁸, —COOR⁹, —CO—R¹⁰ or CN;

R¹ when existent, R², R³, R⁴ and R⁵ are the same or different and eachis independently hydrogen, halogen, hydroxy, thiol, amino, nitro,nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide,alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxyderivative, thio derivative, amino derivative, acyl derivative, sulfonylderivative or sulfinyl derivative,

provided that at least one of the substituents R chosen from R¹ whenexistent, R², R³, R⁴ or R⁵ is not hydrogen;

R⁶ is hydrogen, alkyl, aryl or —CH₂—R^(6a) wherein R^(6a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

R⁷, R⁸ and R⁹ are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R¹⁰ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or athio derivative;

their pharmaceutically acceptable salts, geometrical isomers (includingcis and trans, Z and E isomers), enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one substituent R¹ to R⁵ is differentfrom hydrogen. Some non-substituted compounds are referred to in U.S.Pat. Nos. 5,468,733 and 5,516,759. U.S. Pat. No. 5,468,733 refers tonon-ring substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinylderivatives as inhibitors of the oncogene Ras protein. In particular,these compounds block the ability of Ras to transform normal cells tocancer cells, and therefore can be included in several chemotherapeuticcompositions for treating cancer.

U.S. Pat. No. 5,516,759 refers to non-ring substituted2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivativespresent at the N-terminus of dodecapeptides possessing LHRH (luteinizinghormone-releasing hormone) antagonistic activity. Such LHRH antagonistsare useful in the treatment of a variety of conditions in whichsuppression of sex steroids plays a key role including contraception,delay of puberty, treatment of benign prostatic hyperplasia a. o.

In the definitions set forth below, unless otherwise stated, R¹¹ and R¹²are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl. heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein, is defined as including—O—R¹¹ groups wherein R¹¹ is as defined above except for “oxyderivative”. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy,acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy,arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxysuch as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy,2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative”, as used herein, is defined as including—S—R¹¹ groups wherein R¹¹ is as defined above except for “thioderivative”. Non-limiting examples are alkylthio, alkenylthio,alkynylthio and arylthio.

The term “amino derivative”, as used herein, is defined as including—NHR¹¹ or —NR¹¹R¹² groups wherein R¹¹ and R¹² are as defined above.Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- andarylamino or mixed amino.

The term “acyl derivative”, as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R¹¹—CO—, wherein R¹¹ is as defined above and may also behydrogen. Preferred are acyl derivatives of formula —COR¹¹ wherein R¹¹is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkenyl,heterocyle and aryl. Non-limiting examples are formyl, acetyl,propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl,cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl,furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl,oxamoyl.

The term “sulfonyl derivative”, as used herein, is defined as includinga group of the formula —SO₂—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfonyl derivative”. Non-limiting examples are alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative”, as used herein, is defined as includinga group of the formula —SO—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfinyl derivative”. Non-limiting examples are alkylsulfinyl,alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and generally containing 1-20 carbonatoms, most often 1 to 12 carbon atoms, preferably 1-7 carbon atoms fornon-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these twopreferred cases, unless otherwise specified, “lower alkyl”), eachoptionally substituted by, preferably 1 to 5, substituents independentlyselected from the group consisting of halogen, hydroxy, thiol, amino,nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinylderivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl,sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester,oxyamido, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy(preferably C6-10) and aryl (preferably C6-10).

Preferred are alkyl groups containing 1 to 7 carbon atoms, eachoptionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio,cyclopropyl, acyl and phenyl. Most preferred are C1-4 alkyl and C3-7cycloalkyl, each optionally substituted by one or more hydroxy, halogen,lower alkyl or/and azido.

Most preferred alkyl groups are hydroxymethyl, propyl, butyl,2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl,2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to C₁ to C₇ saturated straight, branched or cyclic hydrocarbon.Non limiting examples are methyl, ethyl, propyl, isopropyl, butyl,tertiobutyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl,hexyl, isohexyl, cyclohexyl, 3-methypentyl, 2,2-dimethylbutyl,optionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferably, lower alkyl is methyl.

The term “alkenyl”, as used herein, is defined as including bothbranched and unbranched, unsaturated hydrocarbon radicals having atleast one double bond, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro,cyano, aryl and heterocycle.

Preferred alkenyl groups are C2-C12 alkenyls, especially C2-6 alkenyls,such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl,1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl,4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl,2-hexenyl and the like, optionally being substituted by one or moresubstituents selected from halogen, cyano, thiocyanato, azido,alkylthio, cycloalkyl, phenyl and acyl. Most preferred is vinyl,optionally substituted by one or more halogen or/and lower alkyl, andespecially 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido,alkylthio, alkyl and acyl.

Preferred alkynyl groups are C2-12 alkynyl, especially C2-6 alkynyl,optionally being substituted by one or more substituents selected fromhalogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl such as phenyland alkyl, preferably cycloalkyl.

Most preferred are ethynyl, propynyl and butynyl, optionally substitutedby lower alkyl or/and halogen, and especially 1-propynyl,cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e. g. “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of at least onering, most often 1 to 3 rings and generally containing 6-30 carbon atomsby removal of one hydrogen, such as phenyl and naphthyl, each optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonicacid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio,oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl,C1-6-haloalkyl. Aryl radicals are preferably monocyclic or bicycliccontaining 6-10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl each optionally substituted by one or more substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkyl, C1-6-haloalkyl, sulfonyl and phenyl.

Preferred aryl is phenyl, optionally substituted by one or more halogen,lower alkyl, azido or nitro, such as 3-chlorophenyl and 3-azidophenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO₂.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “azido”, as used herein, represents a group of the formula —N₃.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO₃H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

The term “ester”, as used herein, is defined as including a group offormula —COO—R¹¹ wherein R¹¹ is as defined above except oxy derivative,thio derivative or amino derivative. Preferred are esters of formula—COOR¹¹ wherein R¹¹ is selected from C1-12 alkyl, C2-12 alkenyl, C2-12alkynyl and aryl. Most preferred are esters where R¹¹ is a lower alkyl,especially methyl.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH₂ or—CONHR¹¹ or —CONR¹¹R¹² wherein R¹¹ and R¹² are as defined above.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl, and optionallybeing substituted with any suitable group, including but not limited toone or more moieties selected from lower alkyl, or other groups asdescribed above for the alkyl groups. Non-limiting examples ofheterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl,triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thiomorpholinyl, thieno (2,3-b) furanyl,furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl,thianthrenyl, benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl,quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenothiazinyl, furazanyl, benzodioxolyl, isochromanyl,indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholino, morpholinyl, 1-oxaspiro (4.5) dec-2-yl, pyrrolidinyl,2-oxo-pyrrolidinyl, sugar moieties (i. e. glucose, pentose, hexose,ribose, fructose, which may also be substituted) optionally substitutedby alkyl or as described above for the alkyl groups. The term“heterocycle” also includes bicyclic, tricyclic and tetracyclic, spirogroups in which any of the above heterocyclic rings is fused to one ortwo rings independently selected from an aryl ring, a cyclohexane ring,a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or anothermonocyclic heterocyclic ring or where a monocyclic heterocyclic group isbridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1) heptanyl, 8-azabicyclo(3.2.1) octanyl.

The heterocycle is preferably selected from triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyland piperazinyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino,acyl and phenyl.

More preferably the heterocycle is selected from tetrazolyl,pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, eachoptionally substituted by one or more substituents selected fromhalogen, alkyl, halogen substituted alkyl, acyl, alkoxy, nitro, aminoand phenyl, and especially from 2- and 3-thienyl, optionally substitutedby one or more halogen, acyl such as formyl, cyano and/or lower alkyl,such as methyl.

In the above definitions it is to be understood that when a substituentsuch as R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰ is attached to the rest ofthe molecule via a heteroatom or a carbonyl, a straight- or branchedchain, C1-12-, preferably C1-4-alkylene or C2-12, preferablyC2-4-alkenylene or -alkynylene bridge may optionally be interposedbetween the heteroatom or the carbonyl and the point of attachment tothe rest of the molecule.

The term “R substituent” refers to R¹, R², R³, R⁴ or R⁵, independently.

According to a preferred embodiment, a compound of formula I is asdefined above wherein n represents 0. The compound is a 6-ring structure(2-thioxo- or 2-oxo-piperidinyl derivative) wherein R¹ is not existentsince n=0, and is depicted by the formula (I-A).

According to a following embodiment, the compound of formula I is asdefined above wherein n represents 1. The compound is a 7-ring structure(2-thioxo- or 2-oxo-azepanyl derivative) wherein R¹ is existent sincen=1 and depicted by the formula (I-B).

According to a more preferred embodiment, said compound is as definedabove wherein n=0, R³ and/or R⁴ are different from hydrogen and R² andR⁵ represent hydrogen.

According to another more preferred embodiment, said compound is asdefined above wherein n=1, R², R³ and/or R⁴ are different from hydrogenand wherein R¹ and R⁵ represent hydrogen.

According to a yet more preferred embodiment, said compound is asdefined above wherein only one R substituent chosen from R³ or R⁴ whenn=0 or from R², R³ or R⁴ when n=1, is different from hydrogen and theremaining R substituent(s) is/are hydrogen. We hereby refer to amono-substituted 2-thioxo- or 2-oxo-piperidinyl or 2-thioxo- or2-oxo-azepanyl derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein A¹ represents an oxygen atom. We hereby refer to2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein X is CONR⁷R⁸, especially CONH₂. We hereby refer toamido derivatives of 2-oxo (or thioxo)-piperidinyl or 2-oxo (orthioxo)-azepanyl.

According to another preferred embodiment, compounds of formula I are asdefined above wherein R⁶ represents hydrogen, C1-4 alkyl, or aCH₂—R^(6a) group wherein R^(6a) represents a heterocycle. Mostpreferably R⁶ is a C1-4 alkyl, especially ethyl. When R⁶ is ethyl werefer to 2-(2-oxo (or thioxo)-1-piperidinyl) butanamide or 2-(2-oxo (orthioxo)-1-azepanyl) butanamide derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein the carbon atom to which R⁶ is attached is of theS configuration. In case where R⁶ is ethyl, A is oxygen and X is CONR⁷R⁸we refer then to (2S)-2-(2-oxo-1-piperidinyl) butanamide or(2S)-2-(2-oxo-1-azepanyl) butanamide derivatives.

According to a preferred embodiment, the compound is as defined abovewherein R² when n=1, R³ and R⁴ are the same or different and each isindependently hydrogen, halogen, nitro, nitrooxy, cyano, carboxy, amido,sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl,heterocycle, acyl derivative, sulfonyl derivative or sulfinylderivative;

R¹ when existent, R² when n=0 and R⁵ are hydrogen;

R⁶ is hydrogen, alkyl, aryl or —CH₂—R^(6a) wherein R^(6a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

According to this preferred embodiment, the compound is generally suchthat when R⁶ is benzyl, X is —COOCH₃ and n=1, R² is different frommethyl when R³ and R⁴ are both hydrogen and R⁴ is different from methylwhen R² and R³ are both hydrogen.

According to another preferred embodiment, the compound is as definedabove wherein R² when n=1, R³ and R⁴ are the same or different and eachis independently hydrogen; cyano; carboxy; amido;

C1-12 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cycloalkyl, acyl, aryl and heterocycle;

C2-12 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl;

C2-12 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl; acyl derivative of formula —CO—R¹¹, wherein R¹¹ is selectedfrom C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl;

ester of formula —CO—O—R¹¹ wherein R¹¹ is selected from C1-12 alkyl,C2-12 alkenyl, C2-12 alkynyl and aryl;

heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl,each optionally substituted by one or more substituents selected fromhalogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl andphenyl;

aryl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino,azido, sulfonyl, aryl and nitro.

According to another preferred embodiment, the compound is as definedabove, wherein R² when n=1, R³ and R⁴ are the same or different and eachis independently hydrogen;

C1-7 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cyclopropyl, acyl and phenyl;

C2-6 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl;

C2-6 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl;

heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl,pyrrolyl, thiazolyl and thienyl, each optionally substituted by one ormore substituents selected from halogen, alkyl, halogen substitutedalkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, halogen substituted alkyl, halogen, alkoxy, amino,azido, sulfonyl, phenyl and nitro.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently C1-4-alkyl or C3-7-cycloalkyl, optionally substituted byone or more halogen, hydroxy, lower alkyl and/or azido.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently vinyl, optionally substituted by one or more halogenor/and lower alkyl.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently ethynyl, propynyl or butynyl, optionally substituted byone or more halogen and/or lower alkyl.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently phenyl, optionally substituted by one or more halogen,lower alkyl, azido and/or nitro.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently 2- or 3-thienyl, optionally substituted by one or morehalogen, acyl, cyano or/and lower alkyl.

According to a particular preferred embodiment, the compound is asdefined above wherein at least one of the R substituents chosen from thegroup R³, R⁴ and R² when n=1 or from the group R³ and R⁴ when n=0, ishydroxymethyl, propyl, butyl, 3,3,3-trifluoropropyl,2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl,2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl,2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl,5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl,3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl,1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl,2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl,2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to yet another preferred embodiment, the compound is asdefined above wherein R¹, R², R⁴ and R⁵ are hydrogen.

According to even another preferred embodiment, the compound is asdefined above wherein R¹, R², R³ and R⁵ are hydrogen.

According to even another preferred embodiment, the compound is asdefined above wherein n=1 and R¹, R³, R⁴ and R⁵ are hydrogen.

In all the above-mentioned scopes when the carbon atom to which R⁶ isattached is asymmetric it is preferably in the “S”-configuration.

Representative compounds useful in the methods and compositions of thisinvention as defined above are selected from the group consisting of

-   2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-propyl-1-piperidinyl)butanamide,-   2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,-   2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,-   2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,-   2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,-   2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,-   2[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,-   2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,-   2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-4-propyl-1-piperidinyl)butanamide,-   2-[2-oxo-4-(3,3,3trifluoropropyl)-1-piperidinyl]butanamide,-   2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,-   2-[2-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,-   2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,-   2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,-   2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,-   2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,-   2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-5-propyl-1-azepanyl)butanamide,-   2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-5-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-5-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide,-   2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-5-(1-propynyl)-1-azepanyl]butanamide,-   2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-6-propyl-1-azepanyl)butanamide,-   2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-6-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide,-   2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyllbutanamide,-   2-[6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide,-   2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-4-propyl-1-azepanyl)butanamide,-   2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-4-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,-   2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,-   2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2,2-tritluoroethyl)-2-oxo-1-azepanyl]butanamide.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,-   (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

iii) International Patent Application WO 2004/087658:

A compound having the formula I or a pharmaceutically acceptable saltthereof or stereoisomeric forms thereof,

wherein

R¹ is hydrogen,

R² is hydrogen or C1-20-alkyl,

R³ is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl,aromatic or non aromatic heterocycle, C1-20-alkoxy, or a group offormula —W—R⁸, R^(3a) is hydrogen, C1-20-alkyl or a group of formula:

or NR³R^(3a) is a group of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; azido; cyano; —S—C1-4-alkyl;—SO—C1-4-alkyl; —SO₂—C1-4-alkyl; —SONH₂; C1-20-alkyl unsubstituted orsubstituted by halogen; or C1-20-alkoxy unsubstituted or substituted byhalogen,

R⁶ is hydrogen, C1-20-alkyl or halogen,

R⁷ is hydrogen, C1-20-alkyl or halogen,

W is C1-12-alkylene, —NH— or —NHC(═O)—,

X is O, S or NH,

Y is O, S, —CR¹²R¹³—, —NR¹⁴— or —C(═O)—,

R⁸ is aryl or heterocycle,

R⁹, R¹⁰, R^(10a) and R¹¹ are independently selected from hydrogen,C1-4-alkyl, halogen, hydroxy or methoxycarbonyl,

or R¹⁰ and R^(10a) together form a C3-6-alkylene,

R¹² is hydrogen, C1-4-alkyl, halogen or hydroxy,

R¹³ is hydrogen,

or CR¹²R¹³ is dioxolanyl,

R¹⁴ is aryl, heterocycle or a group of formula —V—R¹⁵,

V is C₁₋₁₂-alkylene,

R¹⁵ is aryl or heterocycle,

m is 1 to 4,

n is 0 or 1,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(1a) is H.

In another aspect, the compound has the formula I or a pharmaceuticallyacceptable salt thereof or stereoisomeric forms thereof,

wherein

R¹ is hydrogen,

R² is hydrogen or C1-20-alkyl,

R³ is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl,aromatic or non aromatic heterocycle, C1-20-alkoxy, or a group offormula —W—R⁸,

R^(3a) is hydrogen, C1-20-alkyl or a group of formula:

or NR³R^(3a) is a group of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; C1-20-alkyl unsubstituted or substitutedby halogen; or C1-20-alkoxy unsubstituted or substituted by halogen,

R⁶ is hydrogen, C1-20-alkyl or halogen,

R⁷ is hydrogen, C1-20-alkyl or halogen,

W is C1-12-alkylene, —NH— or —NHC(═O)—,

X is O, S or NH,

Y is O, S, —CR¹²R¹³—, —NR¹⁴— or —C(═O)—,

R⁸ is aryl or heterocycle,

R⁹, R¹⁰, R^(10a) and R¹¹ are independently selected from hydrogen,C1-4-alkyl, halogen, hydroxy or methoxycarbonyl,

or R¹⁰ and R^(10a) together form a C3-6-alkylene,

R¹² is hydrogen, C1-4-alkyl, halogen or hydroxy,

R¹³ is hydrogen,

or CR¹²R¹³ is dioxolanyl,

R¹⁴ is aryl, 1 heterocycle or a group of formula —V—R¹⁵,

V is C1-12-alkylene,

R¹⁵ is aryl or heterocycle,

m is 1 to 4,

n is 0 or 1,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(1a) is H.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and containing 1-20 carbon atoms,preferably 1-6 carbon atoms and more preferably 1-4 carbon atoms fornon-cyclic alkyl and 3-8 carbon atoms for cycloalkyl. Alliyl moietiesmay optionally be substituted by 1 to 5 substituents independentlyselected from halogen, hydroxy, alkoxy, alkoxycarbonyl, ester oralkylamino. Preferred alkyl groups are methyl, ethyl, n-propyl,isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, 3-hydroxypropyl,3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl) propyl,3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and3-(dimethylamino) propyl.

The term “cycloalkyl”, as used herein, refers to a monovalent group of 3to 18 carbon atoms, preferably 4-8 carbon atoms, derived from asaturated cyclic or polycyclic hydrocarbon which may be substituted byany suitable group including but not limited to one or more moietiesselected from groups as described above for the alkyl groups. Preferredcycloalkyl group is cycloheptyl.

The term “alkylene”, as used herein, represents a divalent alkyl group,having straight or branched moieties, containing 1-12 carbon atoms,preferably 1-6 carbon atoms, and being optionally substituted with anysuitable group, including but not limited to one or more moietiesselected from groups as described above for the alkyl groups. Preferredalkylene groups are methylene, ethylene, hydroxyethylene, trimethyleneor propylene.

The term “cycloalkenyl”, as used herein, is defined as a cyclicunsaturated hydrocarbon radical having at least one double bond,containing 4-20 carbon atoms, preferably 5-8 carbon atoms, and beingoptionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferred cycloalkenyl group is6-(hydroxymethyl)cyclohex-3-en-1-yl.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of 1-3 rings andcontaining 6-30 carbon atoms by removal of one hydrogen, such as phenyland naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, hydroxy, nitro, C1-6-alkyl,C1-6-alkoxy, C1-6-alkylsulfonyl, trifluoromethylthio or pyridinylalkyl.Aryl radicals are preferably phenyl radicals. Preferred aryl groups arephenyl, 3-hydroxyphenyl, 3-fluorophenyl, 3-methylphenyl, 4-methylphenyl,4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl,3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl,4-methylsulfonylphenyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl,2-[(trifluoromethyl)thio]phenyl, 2-chlorophenyl or 4-bromophenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “alkoxy”, as used herein, represents a group of formula —OR¹¹wherein R^(b) is an alkyl group, as defined above.

The term “ester”, as used herein, represents a group of formula—COOR^(C) wherein R^(c) is an alkyl group or an aryl group, as definedabove.

The term “alkoxycarbonyl”, as used herein, represents a group of formula—COOR^(d) wherein R^(d) is an alkyl group, as defined above.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “alkylamino”, as used herein, represents a group of formula—NHR² or —NR²R^(f) wherein R² and R^(f) are alkyl group as definedabove.

The term alkylsulfonyl, as used herein is defined as representing agroup of formula —SO₂—R^(g), wherein R^(g) is C1-4-alkyl.

The term “heterocycle”, as used herein is defined as including anaromatic or non aromatic cycloalkyl or cycloalkenyl moiety as definedabove, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl.

Non-limiting examples of aromatic heterocycles are pyrazolyl, furyl,imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl,isothiazolyl, benzimidazolyl, tetrazolyl, isooxazolyl, oxazolyl,thiazolyl, 1,2,4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl,pyrazinyl, isoindolyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolizinyl,naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl,indolyl, indolizinyl, purinyl, carbazolyl, thieno (2,3-b) furanyl,thianthrenyl, benzothiazolyl, benzoxazolyl, cinnolinyl, quinoxalinyl,phenothiazinyl, isochromanyl and xanthenyl, optionally substituted by 1to 5 substituents independently selected from halogen, hydroxy, thiol,amino, nitro, cyano, azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl,C1-6-haloalkyl, formyl or ester. More preferred aromatic heterocyclesare pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl and pyridinyl.

Non-limiting examples of non aromatic heterocycles aretetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl,tetrahydrobenzazocinyl, dihydroisochromenyl, tetrahydropyranyl,oxooctahydroquinolinyl, dioxolanyl, 1-oxaspiro(4.5) dec-2-yl,pyrrolidinyl, 2-oxo-pyrrolidinyl, 8-thiabicyclo[3.2.1]cyclooctanyl,1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl,optionally substituted by 1 to 5 substituents independently selectedfrom halogen, hydroxy, thiol, amino, nitro, cyano, azido, C1-6-alkoxy,C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl, formyl or ester. Morepreferred non aromatic heterocycles are tetrahydrofuranyl, piperidinyl,piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, thiazolidinyl, indolinyl,tetrahydro-1-benzazocin-1(2H)-yl, 3,4-dihydro-1H-isochromen-1-yl,tetrahydropyranyl, oxooctahydroquinolinyl and dioxolanyl. The term“heterocycle” also includes bicyclic, tricyclic and tetracyclic, spirogroups in which any of the above heterocyclic rings is fused to one ortwo rings independently selected from an aryl ring, a cycloalkyl ring, acycloalkenyl ring or another monocyclic heterocyclic ring or where amonocyclic heterocyclic group is bridged by an alkylene group, such asquinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyland 8-azabicyclo(3.2.1)octanyl.

The term “pyridinylalkyl”, as used herein, represents a group of formula—R^(h)-pyridinyl in which R^(h) is C1-4-alkylene.

The term “azido” as used herein, represents a group of the formula —N₃.

The term “cyano” as used herein, represents a group of the formula —CN.Generally, R² is hydrogen or C1-4-alkyl.

Preferably, R² is hydrogen, methyl or ethyl. More preferably, R² ishydrogen or methyl.

Generally, R³ is hydrogen; C1-6-alkyl unsubstituted or substituted by 1to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonylor alkylamino; C5-7-cycloalkyl; (hydroxymethyl)cyclohexenyl; phenylunsubstituted or substituted by 1 to 5 substituents selected fromhalogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl,trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted orsubstituted by methoxy; triazolyl; C1-4-alkoxy; or a group of formula—W—R⁸ wherein:

Generally, W is C1-4-alkylene unsubstituted or substituted by halogen,hydroxy, C1-4-alkyl or alkoxy; —NH—; or —NHC(═O)—; and

R⁸ is phenyl unsubstituted or substituted by 1 to 5 substituentsselected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro,methylsulfonyl or trifluoromethylthio; furyl unsubstituted orsubstituted by methyl; pyrazolyl; pyridinyl; morpholinyl;tetrahydrobenzazocinyl; piperidinyl unsubstituted or substituted bymethyl; dihydroisochromenyl or dihydroimidazolyl.

Preferably, R³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl,3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl) propyl,3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl,3-(dimethylamino) propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl,3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl,3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl,4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl,2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl,2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino,pyridin-3-yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl,pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl)propyl,2-morpholin-4-ylethyl, 2-((3,4,5,6-tetrahydro-1-benzazocin-1 (2H)-yl)propyl, 2-(2-methylpiperidin-1-yl)ethyl,3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino or 4,5-dihydro-1H-imidazol-2-ylamino. More preferably, R³ ishydrogen.

Generally, R^(3a) is hydrogen, C1-4-alkyl or a group of formula

wherein m is 1 to 4.

Preferably, R^(3a) is hydrogen, methyl or tetrahydrofuran-2-ylmethyl.More preferably, R^(3a) is hydrogen.

In another embodiment, NR³R^(3a) is piperidinyl unsubstituted orsubstituted by hydroxy; thiomorpholinyl; thiazolidinyl unsubstituted orsubstituted by C1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl;1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or agroup of formula

wherein R¹⁴ is pyridinyl; phenyl unsubstituted or substituted byhalogen, hydroxy, C1-4-alkyl; or a group of formula —V—R¹⁵ wherein V isunsubstituted C1-4-alkylene and R¹⁵ is phenyl or morpholinyl.

In a preferred embodiment, NR³R^(3a) is 4-pyridin-2-ylpiperazin-1-yl,4-(3-methylphenyl) piperazin-1-yl, 4-(4-hydroxyphenyl) piperazin-1-yl,4-(2-phenylethyl) piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl,4-methoxycarbonyl-1,3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl,1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 4-oxooctahydro-1(2H)-quinolinyl.

Generally, R⁵ is hydrogen, nitro, halogen, C1-4-alkyl, unsubstituted orsubstituted by halogen, or C1-4-alkoxy unsubstituted or substituted byhalogen.

Preferably, R⁵ is hydrogen, methyl, ethyl, trifluoromethyl,trifluoromethoxy, n-propyl, isopropyl, nitro, or halogen. Morepreferably, R⁵ is halogen or trifluoromethyl.

Generally, R⁶ is hydrogen, C1-6-alkyl or halogen.

Preferably, R⁶ is hydrogen, methyl or Cl. More preferably, R⁶ ishydrogen.

Generally, R⁷ is hydrogen, methyl or halogen.

Preferably, R⁷ is hydrogen, methyl, Br, F or Cl. More preferably, R⁷ ishydrogen, Br or F.

Combinations of one or more of these preferred compound groups areespecially preferred.

In a preferred embodiment, the compound has the formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof,

wherein R¹ is hydrogen,

R² is hydrogen or C1-4-alkyl,

R³ is hydrogen; C1-6-alkyl unsubstituted or substituted by 1 to 5substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl oralkylamino; C5-7-cycloalkyl; (hydroxymethyl) cyclohexenyl; phenylunsubstituted or substituted by 1 to 5 substituents selected fromhalogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl,trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted orsubstituted by methoxy; triazolyl; C1-4-alkoxy; or a group offormula—W—R⁸,

R^(3a) is hydrogen, C1-4-alkyl or a group of formula

or NR³R^(3a) is piperidinyl unsubstituted or substituted by hydroxy;thiomorpholinyl; thiazolidinyl unsubstituted or substituted byC1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl;1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or agroup of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; C1-4-alkyl, unsubstituted or substitutedby halogen; or C1-4-alkoxy unsubstituted or substituted by halogen,

R6 is hydrogen, C1-6-allyl or halogen,

R7 is hydrogen, methyl or halogen,

W is C1-4-alkylene unsubstituted or substituted by halogen, hydroxy,C1-4-alkyl or alkoxy; —NH—; or —NHC(═O)—,

R8 is phenyl unsubstituted or substituted by 1 to 5 substituentsselected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro,methylsulfonyl or trifluoromethylthio; furyl unsubstituted orsubstituted by methyl; pyrazolyl; pyridinyl; morpholinyl;tetrahydrobenzazocinyl; piperidinyl unsubstituted or substituted bymethyl; dihydroisochromenyl or dihydroimidazolyl,

R¹⁴ is pyridinyl; phenyl unsubstituted or substituted by halogen,hydroxy, C1-4-alkyl; or a group of formula—V—R¹⁵,

V is unsubstituted C1-4-alkylene,

R¹⁵ is phenyl or morpholinyl,

m is 1 to 4,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

In a more preferred embodiment, the compound has the formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof,

wherein

R¹ is hydrogen,

R² is hydrogen, methyl or ethyl,

R³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl,3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl) propyl,3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl,3-(dimethylamino) propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl,3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl,3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl,4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl,2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl,2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino,pyridin-3-yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl,pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl)propyl, 2-morpholin-4-ylethyl,2-((3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl) propyl,2-(2-methylpiperidin-1-yl)ethyl, 3,4-dihydro-1H-isochromen-1-ylmethyl,methoxy, (4-pyridinylcarbonyl) amino or4,5-dihydro-1H-imidazol-2-ylamino,

R^(3a) is hydrogen, methyl or tetrahydrofuran-2-ylmethyl, or NR³R^(3a)4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl) piperazin-1-yl,4-(4-hydroxyphenyl) piperazin-1-yl, 4-(2-phenylethyl) piperazin-1-yl,4-(2-morpholin-4-ylethyl) piperazin-1-yl, 3-hydroxypiperidin-1-yl,thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidin-3-yl,2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or4-oxooctahydro-1(2H)-quinolinyl,

R⁴ is hydrogen,

R5 is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy,n-propyl, isopropyl, nitro or halogen,

R⁶ is hydrogen, methyl or Cl,

R⁷ is hydrogen, methyl, Br, F or Cl,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

More preferably, R² is hydrogen or methyl, R³ is hydrogen, R^(3a) ishydrogen, R⁵ is halogen or trifluoromethyl, R⁶ is hydrogen and R⁷ ishydrogen, Br or F.

In all the above-mentioned scopes, when R² is C1-20-alkyl, the carbonatom to which R² is attached is preferably in the “S”-configuration.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5,7-dibromo-2-oxo-2,3-dthydro-1H-indol-1-yl) acetamide;2-(5-nitro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;(2R)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;2-[2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-1-yl]acetamide;2-(5-isopropyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(2-oxo-5-propyl-2,3-dihydro-1H-indol-1-yl) acetamide;2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide;2-(5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(7-chloro-2-oxo-2,3-dihydro-IH-indol-1-yl) acetamide;2-(6-chloro-2-oxo-2,3-dihydro-IH-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) butanamide;(+)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) butanamide;(−)-2-(5-chloro-2-oxo-2,3-dihydro-IH-indol-1-yl) butanamide;2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;(+)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;(−)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;(−)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;(+)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxyphenyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-fluorophenyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(2-pyridin-2-ylethyl)phenyllacetarnide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[6-(hydroxymethyl)cyclohex-3-en-1-yl]acetanuide;5-chloro-1-[2-oxo-2-(4-pyridin-2-ylpiperazin-1-yl)ethyl3-1,3-dihydro-2H-indol-2-one;5-chloro-1-{2-[4-(3-methylphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)-N-(tetrahydrofuran-2-ylmethyl)acetamide;5-chloro-1-[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N′-isonicotinoylacetohydrazide;5-chloro-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4H-1,2,4-triazol-3-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[4-(methylsulfonyl)benzyl]acetamide;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]octahydroquinolin-4(1H)-one;N′-(4-bromophenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetohydrazide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(6-methoxypyridin-3-yl)acetamide; N-butyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxypropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(dimethylamino)propyl]acetamide;5-chloro-1-{2-oxo-2[4-(2-phenylethyl)pperazin-1-yl]ethyl}-1,3-dihydro-2H-indol-2-one;ethyl {[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetyl]amino 1acetate; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-ethoxypropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-fluoroethyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methoxy-N-methylacetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dimethylphenyl)acetamide;N-(4-tert-butylphenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[1-(hydroxymethyl)propyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-hydroxy-2-phenylethyl)acetamide; 5-chloro-1-{2-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-furyl)methyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(1H-pyrazol-1-yl)propyl]acetamide;methyl3-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl]acetyl]-1,3-thiazolidine-4-carboxylate;5-chloro-1-[2-(2,5-dihydro-1H-pyrrol-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N′-(4,5-dihydro-1H-imidazol-2-yl)acetohydrazide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-chlorophenyl)etl-lyllacetaniide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(4-methylphenyl)ethyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-morpholin-4-ylethyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-methylpiperidin-1-yl)ethyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-nitrobenzyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dihydro-1H-isochromen-1-ylinethyl)acetamide;N-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;N-benzyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methylacetamide;2-(5-chloro-2-oxo-2,3-dthydro-1H-indol-1-yl)-N-{2-[(trifluoromethyl)thio]benzyl}acetamide;5-chloro-1-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-cycloheptylacetamide;5-chloro-1-{2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; and2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3-ylacetamide.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide and2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide.

In another embodiment, compounds useful in the methods and compositionsof this invention are selected from the group consisting of:2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide and(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide.

iv) U.S. Pat. No. 7,244,747:

A compound having the formula I or a pharmaceutically acceptable saltthereof,

wherein R¹ is hydrogen, C₁₋₂₀ alkyl, C₃₋₈ cycloalkyl, halogen, hydroxy,alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, aminoderivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,alkylsulfinyl, arylsulfinyl, aryl or heterocycle;

R² is hydrogen, C₁₋₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;

R³ is hydrogen, C₁₋₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁴ is hydrogen, C₁₋₂₀ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, aryl, azido,alkoxycarbonylamino, arylsulfonyloxy or heterocycle;

R^(4a) is hydrogen or C₁₋₂₀ alkyl;

or R⁴ and R^(4a) can form together a C₃₋₈ cycloalkyl;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R⁶ is hydrogen or C₁₋₂₀ alkyl;

R⁷ is hydrogen;

or R⁶ and R⁷ are linked together to form a C₃₋₆ cycloalkyl;

R⁸ is hydrogen, halogen, nitro, cyano, C₁₋₂₀ alkyl or alkoxy;

R⁹ is hydrogen, C₁₋₂₀ alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R¹⁰ is hydrogen, C₁₋₂₀ alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R¹¹ is hydrogen, halogen, nitro, cyano, C₁₋₂₀ alkyl or alkoxy;

R¹² is hydrogen or halogen;

R¹³ is hydrogen, nitro, halogen, heterocycle, amino, aryl, C₁₋₂₀ alkylunsubstituted or substituted by halogen, or alkoxy unsubstituted orsubstituted by halogen;

R¹⁴ is hydrogen, C₁₋₂₀ alkyl or halogen;

R¹⁵ is hydrogen, C₁₋₂₀ alkyl or halogen;

with the proviso that R⁴ is different from hydrogen when represents agroup of formula

The asterisk * indicates the point of attachment of the substituents.

In a preferred embodiment, the compounds have the formula I, theirtautomers, geometrical isomers (including cis and trans, Z and Eisomers), enantiomers, diastereoisomers and mixtures thereof (includingall possible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein R¹ is hydrogen, C₁₋₂₀ alkyl, C₃₋₈ cycloalkyl, halogen, hydroxy,ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl,alkylsulfinyl, aryl or heterocycle;

R² is hydrogen, C₁₋₂₀ alkyl, halogen, cyano, ester, carbamate or amido;

R³ is hydrogen, cyano, C₁₋₂₀ alkyl, halogen or ester;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁴ is hydrogen, C₁₋₂₀ alkyl, C₂₋₁₂ alkenyl or aryl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R⁶ is hydrogen or C₁₋₂₀ alkyl;

R⁷ is hydrogen; or R⁶ and R⁷ are linked together to form a C₃₋₆cycloalkyl;

R⁸ is hydrogen;

R⁹ is hydrogen, C₁₋₂₀ alkyl, halogen or alkoxy;

R¹⁰ is hydrogen, C₁₋₂₀ alkyl, halogen or cyano;

R¹¹ is hydrogen;

R¹² is hydrogen or halogen;

R¹³ is hydrogen, halogen, heterocycle or C₁₋₂₀ alkyl;

R¹⁴ is hydrogen;

R¹⁵ is hydrogen;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

The term “alkyl”, as used herein, represents saturated, monovalenthydrocarbon radicals having straight (unbranched) or branched or cyclicor combinations thereof and containing 1-20 carbon atoms, preferably1-10 carbon atoms, more pre preferred alkyl groups have 1-3 carbonatoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhalogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkythio,alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl or aryl. Usually alkyl groups, in the presentcase, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl,trifluoromethyl, 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl,(acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl,(4-chlorophenoxy)methyl, benzyl, 2-phenylethyl or 2-(methylthio)ethyl.Preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl,azidomethyl, (acetylamino)methyl, (propionylamino)methyl,(benzoylamino)methyl or 2-(methylthio)ethyl. More preferred alkyl groupsare methyl, ethyl, n-propyl, i-propyl, n-butyl, azidomethyl ortrifluoromethyl. Most preferred alkyl groups are methyl or n-propyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8 carbon atoms, usually 3-6 carbon atoms derived from a saturatedcyclic hydrocarbon, which may be substituted by any suitable groupincluding but not limited to one or more moieties selected from groupsas described above for the alkyl groups. Preferred cycloalkyl groups arecyclopropyl and cyclohexyl.

The term “alkenyl” as used herein, represents straight, branched orcyclic unsaturated hydrocarbon radicals or combinations thereof havingat least one carbon-carbon double bond, containing 2-12 carbon atoms,preferably usually 2-4 carbon atoms. Alkenyl groups are being optionallysubstituted with any suitable group, including but not limited to one ormore moieties selected from groups as described above for the alkylgroups. Usually an alkenyl group is ethenyl (vinyl) optionallysubstituted by 1 to 3 halogens. Preferred alkenyl group, in the presentcase, is 2,2-difluorovinyl.

The term a “alkynyl” as used herein, represents straight, branched orcyclic hydrocarbon radicals or combinations thereof containing at leastone carbon-carbon triple bond, containing 2-12 carbon atoms, preferably2-6 carbon atoms, and being optionally substituted by any suitablegroup, including but not limited to one or more moieties selected fromgroups as described above for the alkyl groups. Preferably an alkynylgroup is a halogenoalkynyl group (haloalkynyl group).

Groups qualified by prefixes such as “s”, “i”, “t” and the like (e.g.“i-propyl”, “s-butyl”) are branched derivatives.

The term “aryl” as used herein, is defined as phenyl optionallysubstituted by 1 to 4 substituents independently selected from halogen,cyano, alkoxy, alkylthio, C₁₋₃ alkyl or azido, preferably halogen orazido. Usually aryl groups, in the present case are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or3-azido-2,4,6-trifluorophenyl. Preferably, aryl groups are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferred arylgroups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cycloalkyl moiety as defined above, having atleast one O, S and/or N atom interrupting the carbocyclic ringstructure. Heterocyclic ring moieties can be optionally substituted byalkyl groups or halogens and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Usuallyheterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl,1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl,4-chloro-1-methyl-1H-pyrazol-3-yl,5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl,3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl,4-methyl-1H-imidazol-5-yl, or 2-methyl-1,3-thiazol-4-yl. Preferredheterocycles are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl,1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrol-2-yl,1H-pyrrol-2-yl.

The term “halogen”, as used herein, includes an atom of chlorine,bromine, fluorine, iodine. Usually halogens are chlorine, bromine andfluorine. Preferred halogens are fluorine, bromine and chlorine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “alkoxy”, as used herein, represents a group of formula —OR^(a)

wherein R^(a) is an alkyl group, as defined above. Preferred alkoxygroup is methoxy.

The term “aryloxy”, as used herein, represents a group of formula —OR¹¹wherein R^(b) is an aryl group, as defined above. Preferred aryloxygroup is phenoxy.

The term “ester”, as used herein, represents a group of formula—COOR^(c) wherein R^(c) is an alkyl group or aryl group, as definedabove. Preferred ester group is methoxycarbonyl.

The term “amido”, as used herein, represents a group of formula —CONH₂.

The term “amino”, as used herein, represents a group of formula —NH₂.

The term “aminoderivative”, as used herein, represents an alkylamino oran arylamino group, wherein the terms “alkyl” and “aryl” are defined asabove.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “nitro”, as used herein, represents a group of formula —NO₂.

The term “azido”, as used herein, represents a group of formula —N₃.

The term “guanidine”, as used herein, represents a group of formula—NHC(═NH)NH₂.

The term “alkylthio”, as used herein, represents a group of formula—SR^(d) wherein R^(d) is an alkyl group, as defined above. Preferredalkylthio group is methylthio.

The term “alkylsulfonyl”, as used herein, represents a group of formula—S(═O)₂R^(e) wherein R^(e) is an alkyl group, as defined above.Preferred alkylsulfonyl group is methylsulfonyl.

The term “alkylsulfinyl”, as used herein, represents a group of formula—S(═O)R^(f) wherein R^(f) is an alkyl group, as defined above. Preferredalkylsulfinyl group is methylsulfinyl.

The term “arylthio”, as used herein, represents a group of formula—SR^(g) wherein R^(g) is an aryl group, as defined above.

The term “arylsulfonyl”, as used herein, represents a group of theformula —S(═O)₂R^(h) wherein R^(h) is an aryl group, as defined above.

The term “arylsulfinyl”, as used herein, represents a group of theformula —S(═O)R^(i) wherein R^(i) is an aryl group, as defined above.

The term “carbamate” as used herein, represents a group of formula—N(H)C(O)OR^(j), wherein R^(j) is an alkyl or an aryl, as defined above.Usually carbamate groups are (propoxycarbonyl)amino or(benzyloaxycarbonyl)amino. Preferred carbamate group is(benzyloaxycarbonyl)amino.

The term “alkanoylamino” as used herein, represents a group of theformula —NHC(═O)R^(k) wherein R^(k) is an alkyl group, as defined above.

The term “(arylcarbonyl)amino” as used herein, represents a group of theformula —NHC(═O)R¹⁰ wherein R¹⁰ is an aryl group, as defined above.Preferred (arylcarbonyl)amino is benzoylamino.

Usually, R¹ is hydrogen; C₁₋₁₀ alkyl unsubstituted or substituted byhalogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy;C₃₋₆ cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl groups; or guanidine. Preferably, R¹ is hydrogen;methyl; ethyl; i-propyl; n-propyl; cyclopropyl; n-butyl; i-butyl;t-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl;chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl;2-(methylthio)ethyl; chloro; bromo; nitro; cyano; amino; aminocarbonyl;methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl;2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl;1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. Morepreferably, R¹ is hydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl;methylthio; nitro; cyano; amino; chloro or 1H-pyrrol-2-yl. Mostpreferably, R¹ is hydrogen; methyl; methylthio; nitro; cyano; amino orchloro.

Usually, R² is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-N-methyl)amino]carbonyl. Preferably, R² ishydrogen; methyl; hydroxymethyl; (acetylamino)methyl;(propionylamino)methyl; (benzoylamino)methyl;[(benzyloxy)carbonyl]amino; chloro or cyano. More preferably, R² ishydrogen; chloro or cyano.

Usually, R³ is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano. Preferably, R³ is hydrogen;hydroxymethyl; chloro; cyano. More preferably, R³ is hydrogen or cyano.Most preferred R³ is hydrogen.

Usually, R⁴ is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhalogens; C₂₋₄ alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens. Preferably, R⁴ ishydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl;3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Morepreferably, R⁴ is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R⁴is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or3-azido-2,4-difluorophenyl.

Usually, R^(4a) is hydrogen.

Usually, R⁵ is hydrogen.

Usually, R⁶ is hydrogen or C₁₋₁₀ alkyl unsubstituted or substituted byhydroxy or azido. Preferably, R⁶ is hydrogen or azidomethyl. Morepreferably R⁶ is hydrogen.

Usually R⁷ is hydrogen.

In other preferred embodiments, R⁶ and R⁷ are linked to form acyclopropyl.

In other preferred embodiments, R² and R³ can form together with theimidazole ring the following 1H-benzimidazole cycle

Usually, R⁸ is hydrogen.

Usually, R⁹ is hydrogen; halogen; C₁₋₃ alkyl or alkoxy. Preferably, R⁹is hydrogen; methyl; chloro or methoxy. More preferred R⁹ is hydrogen.

Usually, R¹⁰ is hydrogen; halogen; cyano; C₁₋₃ alkyl unsubstituted orsubstituted by halogens; or alkoxy. Preferably, R¹⁰ is methyl; hydrogen;trifluoromethyl; fluoro; cyano or methoxy. More preferred R¹⁰ ishydrogen; trifluoromethyl; fluoro or cyano.

Usually, R¹¹ is hydrogen.

In other preferred embodiments, R⁴, R^(4a) and R⁵ can form together withthe 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-onecycle

Usually, R¹² is hydrogen or halogen. Preferably R¹² is hydrogen; chloroor fluoro. More preferred R¹² is hydrogen.

Usually, R¹³ is hydrogen; C₁₋₃ alkyl; halogen or thiazolyl unsubstitutedor substituted by alkyl groups, such as methylthiazolyl. Preferably R¹³is hydrogen; chloro; bromo or methyl. Most preferred R¹³ is chloro;bromo or methyl.

Usually R¹⁴ is hydrogen.

Usually, R¹⁵ is hydrogen.

Combinations of one or more of these preferred compound groups areespecially preferred.

Generally, among the embodiments, the compounds of formula I, orpharmaceutically acceptable salts thereof, are those wherein

R¹ is selected from hydrogen; C₁₋₁₀ alkyl unsubstituted or substitutedby halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C₃₋₆cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl group; or guanidine;

R² is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate or [(N-methoxy-N-methyl)amino]carbonyl.

R³ is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano;

R⁴ is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhalogens; C₂₋₄ alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens;

R^(4a) is hydrogen;

R⁵ is hydrogen;

R⁶ is selected from hydrogen or C₁₋₁₀ alkyl unsubstituted or substitutedby hydroxy or azido;

R⁷ is hydrogen;

or R⁶ and R⁷ can be linked to form a cyclopropyl;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is selected from hydrogen; halogen; C₁₋₃ alkyl; alkoxy;

R¹⁰ is selected from hydrogen; halogen; cyano or C₁₋₃ alkylunsubstituted or substituted by halogens; or alkoxy;

R¹¹ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹² is selected from hydrogen or halogen;

R¹³ is selected from hydrogen; C₁₋₃ alkyl; halogen; thiazolylunsubstituted or substituted by alkyl groups, such as methylthiazolyl;

R¹⁴ is hydrogen;

R¹⁵ is hydrogen;

-   -   with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl;2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl;hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chloro;bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl;1,2,3-thiadiazol-4-yl; or 1H-imidazol-2-yl;

R² is selected from hydrogen; methyl; hydroxymethyl;(acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl;(benzyloxycarbonyl)amino; chloro; or cyano;

R³ is selected from hydrogen; hydroxymethyl; chloro; cyano;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is selected from hydrogen; methyl; choro; methoxy;

R¹⁰ is selected from methyl; hydrogen; trifluoromethyl; fluoro; cyano;or methoxy;

R¹¹ is hydrogen;

R⁴ is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl; or3-azido-2,4,6-trifluorophenyl.

R^(4a) is hydrogen; R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹² is selected from hydrogen; chloro; fluoro;

R¹³ is selected from hydrogen; chloro; bromo; methyl;

R¹⁴ is hydrogen;

R¹⁵ hydrogen;

R⁶ is selected from hydrogen; azidomethyl;

R⁷ is hydrogen;

or R⁶ and R⁷ are linked to form a cyclopropyl;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a more preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;n-butyl; methylthio; nitro; cyano; amino; chloro; or 1H-pyrrol-2-yl;

R² is selected from hydrogen; chloro; cyano;

R³ is selected from hydrogen; cyano;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is hydrogen;

R¹⁰ is selected from hydrogen; trifluoromethyl; fluoro; cyano;

R¹¹ is hydrogen;

R⁴ is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl; or 3-azido-2,4-difluorophenyl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

wherein

R¹² is hydrogen;

R¹³ is selected from methyl; chloro; bromo;

R¹⁴ is hydrogen;

R¹⁵ hydrogen;

R⁶ is hydrogen;

R⁷ is hydrogen;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a most preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; methylthio; nitro; cyano; amino;chloro;

R² is selected from hydrogen; chloro; cyano;

R³ is hydrogen;

R⁴ is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹² is hydrogen;

R¹³ is selected from chloro; bromo; methyl;

R¹⁴ is hydrogen;

R¹⁵ hydrogen;

R⁶ is hydrogen;

R⁷ is hydrogen.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;4-(3-azido-2,4,6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(+4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide,4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;methyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxyla-te;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,4-dichloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(5-methyl-2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,5-dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(4-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[4-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;benzyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-5-ylcarbamat-e;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide;1-(1H-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;1-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(chloromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-on-e;{1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}acetoni-trile;1-[(5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one-;1-[(5-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5,6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propyl-pyrrolidin-2-one;1-[(6-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-car-bonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[6-methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-pro-pylpyrrolidin-2-one;1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazole-5-carbonitrile;1-[(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylp-yrrolidin-2-one;1-[(2-isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1,2,3-thiadiazol-4-yl-)-1H-benzimidazole-5-carbonitrile;1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrr-olidin-2-one;1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propyl-pyrrolidin-2-one;4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl-}pyrrolidin-2-one;1-{[2-(3-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propyl-pyrrolidin-2-one;1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-methyl}pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile;and1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-c-arbonitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one,1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(+4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(11H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+);1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-car-bonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbo-nitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-on-e;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbo-nitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one.

v) International Patent Application WO 2007/065595:

Compounds having formula I, their enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers), orpharmaceutically acceptable salts thereof,

wherein

R¹ is hydrogen or C₁₋₆ alkyl;

R² is hydrogen or C₁₋₄ alkyl;

R³ is a group of formula —CHR⁵R⁶ or a benzyl group;

R⁴ is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl, C3-6cycloalkyl, aryl or heterocycle;

R⁵ is C2-4 alkyl;

R⁶ is C2-4 alkyl, amido or —COOR⁷;

R⁷ is C1-4 alkyl;

Usually when R³ is a benzyl group, then R⁴ is C₁₋₈ alkyl optionallysubstituted by alkoxycarbonyl.

Usually when R³ is a group of formula —CHR⁵R⁶ then R⁴ is C₁₋₈ alkyloptionally substituted by C₃₋₆ cycloalkyl, aryl or heterocycle.

The term “alkyl”, as used herein, is a group which represents saturated,monovalent hydrocarbon radicals having straight (unbranched) or branchedmoieties, or combinations thereof, and containing 1-8 carbon atoms,preferably 1-6 carbon atoms; more preferably alkyl groups have 1-4carbon atoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl orheterocycle. Alkyl moieties may be optionally substituted by acycloalkyl as defined hereafter. Preferred alkyl groups are methyl,cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl,2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, i-butyl, n-pentyl,3-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl,(3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. Morepreferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl,n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl,benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl,(3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. Mostpreferred alkyl groups are methyl, ethyl, 3-methoxybenzyl, 3-nitrobenzylor (5-nitro-2-furyl)methyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8, preferably 3 to 6 carbon atoms derived from a saturated cyclichydrocarbon, which may be substituted by any suitable group includingbut not limited to one or more moieties selected from groups asdescribed above for the alkyl groups. Preferred cycloalkyl group iscyclohexyl.

The term “aryl” as used herein, is defined as a phenyl group optionallysubstituted by 1 to 4 substituents independently selected from halogen,amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl,3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

The term “phenyl”, as used herein, represents an aromatic hydrocarbongroup of formula —C₆H₅.

The term “benzyl group”, as used herein, represents a group of formula—CH₂-aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groupsare benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or3-aminobenzyl. Most preferred alkyl groups are 3-methoxybenzyl or3-nitrobenzyl.

The term “halogen”, as used herein, represents an atom of fluorine,chlorine, bromine, or iodine. Preferred halogen is bromine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “amino”, as used herein, represents a group of formula —NH₂.

The term “ethynyl”, as used herein, represents a group of formula —C≡CH.

The term “alkoxy”, as used herein, represents a group of formula —OR^(a)wherein R^(a) is an alkyl group, as defined above. Preferred alkoxygroup is methoxy.

The term “nitro”, as used herein, represents a group of formula —NO₂.

The term “amido”, as used herein, represents a group of formula—C(═O)NH2.

The term “acyl”, as used herein, represents a group of formula—C(═O)R^(b) wherein R^(b) is an alkyl group, as defined here above.Preferred acyl group is acetyl (—C(═O)Me).

The term “alkoxycarbonyl (or ester)”, as used herein, represents a groupof formula —COOR^(c) wherein R^(c) is an alkyl group; with the provisothat R^(c) does not represent an alkyl alpha-substituted by hydroxy.Preferred alkoxycarbonyl group is ethoxycarbonyl.

The term “heterocycle”, as used herein, represents a 5-membered ringcontaining one or two heteroatoms selected from O or N. The heterocyclemay be substituted by one or two C₁₋₄ alkyl or nitro. Preferredheterocycles are (3, 5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). Mostpreferred heterocycle is (5-nitro-2-furyl).

Generally R¹ is hydrogen or C₁₋₆ alkyl. Usually R¹ is hydrogen or C₁₋₆alkyl optionally substituted by hydroxy, alkoxy, cyano, ethynyl,alkoxycarbonyl or acyl. Preferably R¹ is hydrogen, methyl, cyanomethyl,2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl,3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. More preferably R¹ ishydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropylor 2-propynyl. Most preferably R¹ is hydrogen.

Generally R² is hydrogen or C₁₋₄ alkyl. Usually R² is hydrogen orunsubstituted C₁₋₄ alkyl. Preferably R² is hydrogen, methyl or n-butyl.More preferably, R² is methyl.

Generally R³ is a group of formula —CHR⁵R⁶ or a benzyl group. PreferablyR³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl. Most preferably R³ is 1-(ethoxycarbonyl)propyl.

Generally R⁴ is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl,C₃₋₆ cycloalkyl, aryl or heterocycle. Usually R⁴ is C₁₋₈ alkyloptionally substituted by cyclohexyl, phenyl, bromophenyl, aminophenyl,methoxyphenyl, nitrophenyl, aminosulfonylphenyl,3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. PreferablyR⁴ is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. More preferably R⁴is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. Most preferably R⁴is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Generally R⁵ is C₂₋₄ alkyl. Usually R⁵ is unsubstituted C₂₋₄4 alkyl.Preferably R⁵ is ethyl.

Generally R⁶ is C₂₋₄ alkyl, amido or —COOR⁷. Usually R⁶ is unsubstitutedC₂₋₄ alkyl, amido or —COOR⁷. Preferably R⁶ is ethyl, amido orethoxycarbonyl. Most preferably R⁶ is ethoxycarbonyl.

Generally R⁷ is C₁₋₄ alkyl. Usually R⁷ is unsubstituted C₁₋₄ alkyl.Preferably, R⁷ is ethyl.

In some embodiments, the compounds are those having formula I, and theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein

R¹ is hydrogen, C₁₋₆ alkyl optionally substituted by hydroxy, alkoxy,cyano, ethynyl, alkoxycarbonyl or acyl;

R² is hydrogen or unsubstituted C₁₋₄ alkyl;

R³ is a group of formula —CHR⁵ R⁶ or a benzyl group;

R⁴ is C₁₋₈ alkyl optionally substituted by cyclohexyl, phenyl,bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl,aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl orethoxycarbonyl;

R⁵ is unsubstituted C₂₋₄ alkyl;

R⁶ is unsubstituted C₂₋₄ alkyl, amido or —COOR⁷;

R⁷ is unsubstituted C₁₋₄ alkyl;

with the proviso that when R¹ is hydrogen, R² is methyl, R³ is —CHR⁵ R⁶,R⁶ is ethoxycarbonyl and R⁵ is ethyl, then R⁴ is different fromn-propyl, i-propyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl,4-methylbenzyl or 2-phenylethyl.

In the above embodiment, preferably, when R³ is a benzyl group, then R⁴is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, preferably, when R³ is a group of formula—CHR⁵R⁶, then R⁴ is C₁₋₈ alkyl optionally substituted by C₃₋₆cycloalkyl, aryl or heterocycle.

In a preferred embodiment,

R¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-pentyl or n-hexyl;

R² is hydrogen, methyl or n-butyl;

R³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;

R⁴ is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R¹ is hydrogen, R² is methyl and R³ is1-(ethoxycarbonyl)propyl, then R⁴ is different from n-pentyl,3-bromobenzyl or 2-phenylethyl.

In the above embodiment, preferably, when R³ is 3-bromobenzyl, then R⁴is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, preferably, when R³ is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R⁴ isdifferent from 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment,

R¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl,3-hydroxypropyl or 2-propynyl;

R² is methyl;

R³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;

R⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl; with the provisothat when R¹ is hydrogen, R² is methyl and R³ is1-(ethoxycarbonyl)propyl, then R⁴ is different from 3-bromobenzyl.

In the above embodiment, preferably, when R³ is 3-bromobenzyl, then R⁴is 1-(ethoxycarbonyl)propyl;

In the above embodiment, preferably, when R³ is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R⁴ isdifferent from 1-(ethoxycarbonyl)propyl;

In a most preferred embodiment, R¹ is hydrogen; R² is methyl; R³ is1-(ethoxycarbonyl)propyl; and R⁴ is 3-methoxybenzyl, 3-nitrobenzyl or(5-nitro-2-furyl)methyl.

A further embodiment consists in compounds wherein R² is methyl, R³ is agroup of formula —CHR⁵ R⁶ with R⁵ being C₂₋₄ alkyl, R⁶ being amido or—COOR⁷ and R⁷ being methyl or ethyl.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate;and ethyl2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;and ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

In some embodiments, the compounds are those having formula II, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts:

wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;R.sup.5 is hydrogen or C.sub.1-4 alkyl;R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;R.sup.7 is C.sub.1-4 alkyl;

In the above embodiment, in some cases, when R.sup.3 is a benzyl group,then R.sup.4 is C.sub.1-8 alkyl optionally substituted byalkoxycarbonyl.

In the above embodiment, in some cases, when R.sup.3 is a group offormula —CHR.sup.5R.sup.6, then R.sup.4 is C.sub.1-8 alkyl optionallysubstituted by C.sub.3-6 cycloalkyl, aryl or heterocycle.

In some embodiments, the compounds are those compounds of formula II,their enantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts

whereinR.sup.1 is hydrogen or C.sub.1-6 alkyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;R.sup.5 is hydrogen or C.sub.1-4 alkyl;R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;R.sup.7 is C.sub.1-4 alkyl.

In some embodiments, the compounds are compounds of formula II selectedfrom ethyl2-[(7-heptyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]but-anoate;7-(3-bromobenzyl)-3-methyl-8-(propylthio)-3,7-dihydro-1H-purine-2,-6-dione;ethyl2-[(3-methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]but-anoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}butanoate;ethyl2-[(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]but-anoate;7-(3-bromobenzyl)-8-[(3-chloro-2-hydroxypropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}propanoate.

In some embodiments, the compounds are compounds of formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts

whereinR.sup.1 is hydrogen or C.sub.1-6 alkyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;R.sup.5 is C.sub.2-4 alkyl;R.sup.6 is C.sub.2-4 alkyl, amido or —COOR.sup.7;R.sup.7 is C.sub.1-4 alkyl;

In another embodiment, the compounds are compounds having formula II,their enantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

whereinR.sup.1 is hydrogen or C.sub.1-6 alkyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;R.sup.5 is hydrogen or C.sub.1-4 alkyl;R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;R.sup.7 is C.sub.1-4 alkyl;

vi) International Patent Application Publication No. WO2010/144712

In one embodiment, a chemical composition that includes a LEV derivativeof Formula 1 or Formula 2 is disclosed.

n of Formula 2 and L, X, and Y of Formulas 1 and 2 are defined asfollows: a) n is an integer with a value of 0 to 8; b) L is one of thegroup consisting of CH2, CO, NHCO, NHCOO, CONH, NH, O, or S, andcombinations thereof; c) X is an end group, an aromatic group, an arylgroup, or a saturated, unsaturated, substituted, unsubstituted, straightchain, or branched chain aliphatic group having from 1 to 10 carbonand/or hetero chain atoms, the hetero chain atoms being selected fromthe group consisting of oxygen, nitrogen, sulfur, or phosphorus, andcombinations thereof; and d) Y is optional and if present is one of afunctional group selected from group consisting of alcohol amine, amide,carboxylic acid, aldehyde, ester, iminoester, isocyanate,isothiocyanate, anhydride, thiol, thiolacetone, diazonium, NHS, CO—NHS,O—NHS, maleimido; or e) Y is a Yi-Z where Yi is selected from the groupconsisting of COO, CO, O, CONH, NHCO, or NH and Z is an operative group.

In one embodiment of the method, the operative group of Z is selectedfrom the group consisting of detectable labels, antigenic carriers,coupling agents, end groups, proteins, lipoproteins, glycoproteins,polypeptides, polysaccharides, nucleic acids, polynucleotides, teichoicacids, radioactive isotopes, enzymes, enzyme fragments, enzyme donorfragments, enzyme acceptor fragments, enzyme substrates, enzymeinhibitors, coenzymes, fluorescent moieties, phosphorescent moieties,anti-stokes up-regulating moieties, chemiluminescent moieties,luminescent moieties, dyes, sensitizers, particles, microparticles,magnetic particles, solid supports, liposomes, ligands, receptors,hapten radioactive isotopes, and combinations thereof.

vii) International Patent Application Publication No. WO2010/002869

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Z isindependently selected from hydrogen and deuterium; R1 is an n-propylgroup having zero to seven deuterium atoms; R2 is an ethyl group havingzero to five deuterium atoms, and when each R has zero deuterium atoms,at least one Z is deuterium. One embodiment of this invention providescompounds of Formula I wherein R1 is selected from CD3CH2CH2-,CD3CD2CH2-, CD3CH2CD2-, CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- orCH3CH2CH2-. In a more specific embodiment, R1 is CD3CD2CD2- orCD3CD2CH2-. In one aspect of these embodiments, Z1 and Z2 are bothhydrogen. In another aspect of these embodiments, Z1 and Z2 are bothdeuterium. In another embodiment, R2 is selected from CH3CH2-, CD3CH2-,CH3CD2-, or CD3CD2-. In a more specific embodiment, R2 is selected fromCH3CH2- or CD3CD2-. In one aspect of these embodiments, Z1 and Z2 areboth hydrogen. In another aspect of these embodiments, Z1 and Z2 areboth deuterium.

The R and Z variables as described above may be selected and takentogether to provide more specific embodiments of this invention. Forexample, in one embodiment, R1 is CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2-,CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- or CH3CH2CH2-; and R2 is selectedfrom CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect of thisembodiment, R2 is CH3CH2- or CD3CD2-.

In another embodiment, R1 is CD3CD2CD2- or CD3CD2CH2-; and R2 isselected from CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect ofthis embodiment, R2 is CH3CH2- or CD3CD2-.

Examples of specific compounds of this invention include the following:

viii) 20090312333

The compounds of the present invention are those covered by formula (I),their diastereomers and mixtures, or a pharmaceutically acceptable saltthereof

R1 is hydrogen, substituted or unsubstituted C1-12 alkyl, substituted orunsubstituted aryl or substituted or unsubstituted 3-8 memberedheterocycle.R2 is hydrogen. Alternatively, R1 and R2 may be linked together in sucha way to form a C3-6 cycloalkyl.R3 is either(a) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its C atoms, said heterocycle is selected from thegroup consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl;

or R3 is

(b) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its N atoms, said heterocycle is selected from thegroup consisting of:

-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.    R4 in formula (I) is selected from the group comprising or    consisting of hydrogen; C1-12 alkyl optionally substituted by    halogen, C1-4 alkoxy, C1-4 alkylthio, azido, nitrooxy or an aryl;    C2-12 alkenyl optionally substituted by halogen; C2-12 alkynyl    optionally substituted by halogen; azido; alkoxycarbonylamino;    arylsulfonyloxy; a substituted or unsubstituted aryl; or a 3-8    membered substituted or unsubstituted heterocycle;

In a specific embodiment R4 is hydrogen; or R4 is C1-12 alkyl or a C1-6alkyl, optionally substituted by halogen, C1-4 alkoxy, C1-4 alkylthio,azido or nitrooxy; or R4 is C2-12 alkenyl or a C1-6 alkenyl optionallysubstituted by halogen; or R4 is C2-12 alkynyl or a C1-6 alkynyloptionally substituted by halogen; or R4 is alkoxycarbonylamino.

R5 is hydrogen;

Alternatively R4 may form together with R5 and the 2-oxo-1-pyrrolidinering a 1,3-dihydro-2H-indol-2-one ring of the following structure:

The asterisk * indicates the point of attachment of the substituents;

R6 is hydrogen or halogen.R7 in formula (I) is selected from the group comprising or consisting ofhydrogen; nitro; halogen; heterocycle; amino; aryl; C1-12 alkyloptionally substituted by at least one halogen; or C1-12 alkoxyoptionally substituted by at least one halogen.R8 in formula (I) is selected from the group comprising or consisting ofhydrogen, C1-12 alkyl optionally substituted by halogen, or halogen.R9 in formula (I) is selected from the group comprising or consisting ofhydrogen, C1-12 alkyl optionally substituted by halogen, or halogen.

A further aspect of the present invention consists in compounds offormula (I)

whereinR1 and R2 are both hydrogen.

R3 is:

(a) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its C atoms selected from the group consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl.

Alternatively R3 is:

(b) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its N atoms selected from the group consisting of:

-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.    R4 in formula (I) is selected from the group comprising or    consisting of hydrogen; C1-12 alkyl optionally substituted by    halogen or C1-4 alkoxy; C2-12 alkenyl optionally substituted by    halogen; C2-12 alkynyl optionally substituted by halogen. In a    further specific embodiment R4 is n-propyl, 2,2,2-trifluoroethyl,    2-chloro-2,2-difluoroethyl, 2 bromo-2,2-difluoroethyl,    2,2-difluorovinyl.

In another specific embodiment R4 is phenyl, 2,3,5-trifluorophenyl or3-chloro-4-fluorophenyl.

R5 is hydrogen;

A further embodiment of the present invention consists in compounds offormula (I) wherein R4 forms together with R5a1,3-dihydro-2H-indol-2-one ring

The asterisk * indicates the point of attachment of the heteroarylalkylene substituent, and wherein

R6 is hydrogen;R7 is chlorine;R8 is hydrogen;R9 is hydrogen.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a substituted or unsubstituted heterocyclelinked to the rest of the molecule via one of its C atoms and isselected from the group consisting of:

-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of:

-   imidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-pyrazol-4-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1,3-thiazol-5-yl;

Said heterocycles are optionally substituted by e.g. a methyl, n-propyl,trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, iodine,methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclopropylmethoxy, cyclobutylmethoxy, amino, methylamino,cyclopropylamino, cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl, benzylor 3-thienyl.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of: 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl,6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl,6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl,6-chloroimidazo[2,1-b][1,3]thiazol-5-yl,2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl, 5-chloro-1H-imidazol-4-yl,5-bromo-1H-imidazol-4-yl, 4-bromo-1H-imidazol-5-yl,4-chloro-1H-imidazol-5-yl, 1H-imidazol-5-yl, 1-methyl-1H-imidazol-5-yl,4-chloro-1-methyl-1H-imidazol-5-yl, 1H-pyrazol-4-yl,1H-pyrrolo[2,3-b]pyridin-3-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a heterocycle linked to the rest of themolecule via one of its C atoms and is a substituted or unsubstitutedimidazo[1,2-a]pyridin-3-yl. Said imidazo[1,2-a]pyridin-3-yl isoptionally substituted by e.g. a methyl, cyclopropyl, bromine, chlorine,fluorine, iodine.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of: imidazo[1,2-a]pyridin-3-yl,6-methylimidazo[1,2-a]pyridin-3-yl, 2-chloroimidazo[1,2-a]pyridin-3-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a substituted or unsubstituted heterocyclelinked to the rest of the molecule via one of its N atoms and isselected from the group consisting of:

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H-indol-1-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

A specific further embodiment of the present invention consists incompounds of formula (I) wherein R3 is a heterocycle linked to the restof the molecule via one of its N atoms and is selected from the groupconsisting of:

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl;

Said heterocycles may optionally be substituted by trifluoromethyl,cyclopropyl, bromine, chlorine, fluorine, methoxy or cyano.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of 6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl,6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl,1H-pyrrolo[3,2-b]pyridin-1-yl, 2,5-dichloro-1H-pyrrol-1-yl,2-chloro-5-methoxy-1H-benzimidazol-1-yl,5-bromo-2-chloro-1H-benzimidazol-1-yl or2,5-dichloro-1H-benzimidazol-1-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R1, R2 and R5 are hydrogen.

R4 is a C1-6 alkyl optionally substituted by halogen, a C2-6 alkenyloptionally substituted by halogen or C2-12 alkynyl optionallysubstituted by halogen.R3 is selected from the group consisting of;

-   imidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-pyrazol-4-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1,3-thiazol-5-yl;    and optionally substituted by methyl, n-propyl, trifluoromethyl,    cyclopropyl, bromine, chlorine, fluorine, iodine, methoxy, ethoxy,    propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy,    cyclobutylmethoxy, amino, methylamino, cyclopropylamino,    cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl, benzyl or 3-thienyl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R1, R2 and R5 are hydrogen.

R4 is a C1-6 alkyl optionally substituted by halogen, a C2-6 alkenyloptionally substituted by halogen or C2-12 alkynyl optionallysubstituted by halogen.R3 is selected from the group consisting of

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl;    optionally substituted by trifluoromethyl, cyclopropyl, bromine,    chlorine, fluorine, methoxy or cyano.

A further embodiment of the invention consists in compounds of formula(I), their diastereomers and mixtures, or a pharmaceutically acceptablesalt thereof.

R1, R2 and R5 are hydrogen.R3 is a substituted or unsubstituted heterocycle linked to the rest ofthe molecule via one of its C atoms, said heterocycle is selected fromthe group consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl;

Particularly preferred are imidazo[1,2-a]pyridin-3-yl;imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b]pyridazin-3-yl;1H-imidazol-4-yl; 1H-imidazol-5-yl; R4 is a substituted or unsubstitutedphenyl moiety;

A further embodiment of the present invention consists in compounds offormula (I) wherein R1 is hydrogen or C1-12 alkyl;

R2 is hydrogen;R3 is an aromatic 5-membered heterocycle linked to the rest of themolecule via one of its C atoms;R4 is hydrogen, C1-12 alkyl or aryl;R5 is hydrogen;

Alternatively, R4 can form together with R5 and the 2-oxo-1-pyrrolidinering the following 1,3-dihydro-2H-indol-2-one cycle

wherein the asterisk * indicates the point of attachment of thesubstituents;R6 is hydrogen or halogen;

In this embodiment R4 may not be hydrogen when R3 is substituted1H-pyrazol-5-yl. Also this embodiment does not comprise5-(2′-oxo-1′-pyrrolidinyl)methyl-1,3,4-tricarbomethoxy-pyrazole which isdisclosed in A. Padwa et al J. Org. Chem. 2000, 65, 5223-5232 withoutany biological activity though.

In this embodiment wherein R3 is an aromatic 5-membered heterocyclelinked to the rest of the molecule via one of its C atoms, specificmoieties R3 may be selected from 1,3-thiazol-5-yl, 1H-imidazol-4-yl,1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,2-oxo-2,3-dihydro-1,3-thiazol-5-yl, each of them being optionallysubstituted by 1 to 3 substituents independently selected from methyl,chlorine, bromine, amino, methylamino, dimethylamino,(2-oxo-4-propyl-pyrrolidin-1-yl)methyl, 1-pyrrolidinyl, amido, cyano,methoxy, phenyl, 4-methylphenyl-sulfonyl, benzyl or2-(benzylamino)-2-oxoethyl.

In this embodiment, more specific moieties R3 are selected from2-(methylamino)-1,3-thiazol-5-yl; 2-pyrrolidin-1-yl-1,3-thiazol-5-yl;5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl;1-methyl-1H-imidazol-5-yl; 4-bromo-1-methyl-1H-imidazol-5-yl;4-chloro-1H-imidazol-5-yl; 4-chloro-1-methyl-1H-imidazol-5-yl;4-cyano-1-methyl-1H-imidazol-5-yl; 1H-pyrazol-4-yl;3,5-dimethyl-1H-pyrazol-4-yl; 3-methyl-1H-pyrazol-4-yl.

In this embodiment, most specific moieties R3 are selected from5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl;4-bromo-1-methyl-1H-imidazol-5-yl; 4-chloro-1-methyl-1H-imidazol-5-yl;1H-pyrazol-4-yl. Still in this embodiment, a specific moiety R1 isselected from hydrogen or ethyl. Still in this embodiment, a specificmoiety R4 is selected from hydrogen, n-propyl, 2,3,5-trifluorophenyl orphenyl.

A further embodiment of the present invention consists in compoundshaving the specific formula (Ia).

In formula (Ia) the substituent R10 is hydrogen; halogen; C1-4 alkyloptionally substituted by at least one halogen; C1-4 alkoxy;methoxycarbonyl; nitro; amino; alkylamino; amido; or alkanoyl-amino.Preferably R10 is hydrogen.

R11 is hydrogen; halogen; C1-4 alkyl optionally substituted by at leastone halogen; C1-4 alkoxy; methoxycarbonyl; nitro; amino; alkylamino;amido; or alkanoylamino. Preferably R11 is hydrogen.

R4 is C1-4 alkyl optionally substituted by at least one halogen; or C2-4alkenyl optionally substituted by at least one halogen. Preferably R4 isn-propyl.

Still in this aspect of the invention a specific embodiment relates toan embodiment wherein R10 is selected from hydrogen; methyl; fluorine;chlorine; bromine; methoxy; methoxycarbonyl; nitro; or trifluoromethyl,while R11 is selected from hydrogen; methyl; fluorine; chlorine;bromine; methoxy; methoxycarbonyl; nitro; or trifluoromethyl; and R3 isn-propyl.

Specific compounds of the present invention are those selected from thegroup consisting of:

-   1-[(1-methyl-1H-benzimidazol-6-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(1H-benzimidazol-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(8-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-iodoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(7-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6,8-dibromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6,8-dichloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propyl    pyrrolidin-2-one;-   1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-phenylimidazo[1,2-b][1,2,4]triazin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-phenylpyrrolidin-2-one;-   5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one;-   1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(benzyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(dimethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-chloro-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(methylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(ethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[6-pyrrolidin-1-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(cyclopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-(isopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2-fluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2,2-difluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2,2,2-trifluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[2-cyclopropyl-6-(cyclopropylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(3-chloro-4-fluorophenyl)pyrrolidin-2-one;-   1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclobutylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(2-cyclopropyl-6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-ethoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(cyclopropylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclobutylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carbonitrile;-   4-(2,2-difluorovinyl)-1-{[6-thien-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-pyridin-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-[(6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methylimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-phenylpyrrolidin-2-one;-   4-phenyl-1-[(5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;-   1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;-   1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[1-(1H-imidazol-4-yl)propyl]pyrrolidin-2-one;-   1-[(5-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-[(2-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-4-yl}methyl)-4-propylpyrrolidin-2-one;-   1-[(5-chloro-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-imidazol-4-yl)methyl]-5-chloro-1,3-dihydro-2H-indol-2-one;-   1-(1H-imidazol-5-ylmethyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;-   1-methyl-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;-   1-(1H-imidazol-5-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide;-   N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile;-   1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;-   1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   benzyl    1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-2-ylcarbamate;-   1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   5-chloro-1-(1H-imidazol-5-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   1-[(2,4-dichloro-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   5-chloro-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-indol-2-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-indol-3-ylmethyl)-4-propylpyrrolidin-2-one;-   3-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-5-carbonitrile;-   1-[(2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(7-methoxy-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(trifluoromethyl)-1H-indol-3-yl]methyl}pyrrolidin-2-one;-   1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(7-fluoro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloro-2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[1H-indol-3-yl(phenyl)methyl]-4-propylpyrrolidin-2-one;-   1-[1-(1H-indol-3-yl)propyl]-4-propylpyrrolidin-2-one;-   1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   3-[(2-oxo-4-propylpyrrolidin-1-yl)(phenyl)methyl]-1H-indole-5-carbonitrile;-   1-(1H-indol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-indol-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(1-phenyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   4-(2,3,5-trifluorophenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one;-   1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-chloro-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(3-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;-   (−)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   (+)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   5-chloro-1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-1,3-dihydro-2H-indol-2-one;-   1-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(5-amino-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-5-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-methyl-6-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-methyl-6-(1H-pyrrol-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-({6-[(1E)-hex-1-enyl]-2-methylpyrazolo[1,5-a]pyrimidin-3-yl}methyl)-4-propylpyrrolidin-2-one;-   1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-hydroxy-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-propyl-1-(pyridin-3-ylmethyl)pyrrolidin-2-one;-   (−)-1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one;-   5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one;-   1-[(2-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-[(2-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one;-   1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one;-   1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one;-   1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2-pyrrolidin-1-yl-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1,3-thiazol-2(3H)-one;-   4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one;-   4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;-   4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one;-   1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-{[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}-4-phenylpyrrolidin-2-one;-   1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(3-chloro-7H-imidazo[4,5-c]pyridazin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-fluoro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(2,3-dihydro-1H-indol-1-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-2-carbonitrile;-   1-[(2-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,5-dichloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(9H-purin-9-ylmethyl)pyrrolidin-2-one;-   1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(benzylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(propylamino)-9H-purin-9-yl]methyl}pyrrolidin-2-one;-   1-({6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}methyl)-4-propylpyrrolidin-2-one;-   4-propyl-1-[(6-pyrrolidin-1-yl-9H-purin-9-yl)methyl]pyrrolidin-2-one;-   1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)pyrrolidin-2-one;-   1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(8H-isothiazolo[5,4-b]indol-8-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one;-   1-[(2,5-dichloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;-   2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;-   2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-6-carbonitrile;-   4-propyl-1-[(2,5,6-trichloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;-   1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,6-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,5-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;-   1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(pyridin-4-ylmethyl)pyrrolidin-2-one, and-   1-[(2-chloro-5-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one.

viii) U.S. Pat. No. 4,696,943

The present invention relates to the novel compound(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

ix) U.S. Pat. No. 4,696,942

The present invention relates to the novel compound,(R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide

x) U.S. Pat. No. 5,334,720

According to this invention we provide novel compounds of the formula I,

wherein, R1, R2, R3 and R4, which may be the same or differentindependently represent hydrogen, C1-6 alkyl, phenyl or phenylsubstituted by one or more halogen, hydroxyl, nitro, amino, C1-6 alkylor C1-C6 alkoxy groups;R5 and R6 independently represent hydrogen, C1-C6 alkyl or C3-C6cycloalkyl, or R5 and R6 together with the nitrogen form a C4-6 Nheterocycle;m represents an integer from 1-2; andn represents an integer from 1-3;provided that,two of the substituents R1, R2, R3 and R4 independently represent phenylor substituted phenyl and the other two independently represent hydrogenor C1-6 alkyl;or a pharmaceutically acceptable acid addition salt thereof.

Pharmaceutically acceptable acid addition salts of the compounds offormula I include salts of mineral acids, for example, hydrohalic acids,e.g. hydrochloric or hydrobromic; or organic acids, e.g. formic, aceticor lactic acids. The acid may be polybasic, for example sulphuric,fumaric, maleic or citric acid.

This invention also relates to all stereoisomeric forms and opticalenantiomeric forms of the compounds of formula I.

In the compounds of formula I: alkyl groups which R1, R2, R3, R4, R5 andR6 may represent include methyl, ethyl, propyl, isopropyl, n-butyl,iso-butyl and s-butyl;

cycloalkyl groups which R5 and R6 may represent include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl;C1-6 alkoxy groups include methoxy, ethoxy and propoxy;halogen groups include fluorine, chlorine, bromine or iodine;

We prefer compounds of formula I or a pharmaceutically acceptable acidaddition salt thereof, in which;

R1 is hydrogen, phenyl or substituted phenyl, preferably phenyl;R2 is hydrogen, phenyl or substituted phenyl, preferably phenyl;R3 is hydrogen, phenyl or substituted phenyl, preferably hydrogen;R4 is hydrogen, phenyl or substituted phenyl, preferably hydrogen;R5 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydrogen ormethyl;R6 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydrogen ormethyl;m represents an integer from 1-2 preferably 2;n represents an integer from 1-2, preferably 1.

We especially prefer compounds of formula I in which R1 and R2 are bothphenyl.

We especially prefer compounds of formula I in which one of R5 and R6 ishydrogen and the other is hydrogen or methyl.

xi) International Patent Application Publication No. WO2005/054188

In one aspect the invention therefore provides a compound having theformula I or a pharmaceutically acceptable salt thereof,

whereinRI is hydrogen, CI-20 alkyl, C3 23 cycloalkyl, halogen, hydroxy, alkoxy,aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative,alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,arylsulfinyl, aryl or heterocycle; R2 is hydrogen, C1 20 alkyl, alkoxy,amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;R3 is hydrogen, C1 20 alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;or R2 and R3 can form together with the imidazole ring the following1H-benzimidazole cycle

R4 is hydrogen, C1-20 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl, azido,alkoxycarbonylamino, arylsulfonyloxy or heterocycle; R4a is hydrogen orC1-20 alkyl; or R4 and R4a can form together a C3-8 cycloalkyl; R5 ishydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R6 is hydrogen or C1 20 alkyl; R7 is hydrogen; or R6 and R7 are linkedtogether to form a C3-6 cycloalkyl; R8 is hydrogen, halogen, nitro,cyano, C1 20 alkyl or alkoxy; R9 is hydrogen, C1-20 alkyl, halogen,hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, aminoderivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,alkylsulfinyl or arylsulfinyl;RIO is hydrogen, C1 20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;RI 1 is hydrogen, halogen, nitro, cyano, C1 20 alkyl or alkoxy; R12 ishydrogen or halogen;R13 is hydrogen, nitro, halogen, heterocycle, amino, aryl, C1-20 alkylunsubstituted or substituted by halogen, or alkoxy unsubstituted orsubstituted by halogen; R14 is hydrogen, C1-20 alkyl or halogen;R15 is hydrogen, C1 20 alkyl or halogen;with the proviso that R4 is different from hydrogen when

N represents a group of formula

The asterisk * indicates the point of attachment of the substituents.

In a preferred embodiment, the invention concerns a compound having theformula I, their tautomers, geometrical isomers (including cis andtrans, Z and E isomers), enantiomers, diastereoisomers and mixturesthereof (including all possible mixtures of stereoisomers), orpharmaceutically acceptable salts thereof,

whereinRI is hydrogen, C1-20 alkyl, C3-8 cycloalkyl, halogen, hydroxy, ester,amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl,alkylsulfinyl, aryl or heterocycle; R2 is hydrogen, C1 20 alkyl,halogen, cyano, ester, carbamate or amido; R3 is hydrogen, cyano, C1 20alkyl, halogen or ester; or R2 and R3 can form together with theimidazole ring the following 1H-benzimidazole cycle

R4 is hydrogen, C1 20 alkyl, C2 12 alkenyl or aryl; R4a is hydrogen;R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R6 is hydrogen or C1 20 alkyl; R7 is hydrogen; or R6 and R7 are linkedtogether to form a C3-6 cycloalkyl; R8 is hydrogen; R9 is hydrogen,C1-20 alkyl, halogen or alkoxy; RIO is hydrogen, C1 20 alkyl, halogen orcyano; R11 is hydrogen; R12 is hydrogen or halogen; R13 is hydrogen,halogen, heterocycle or C1 20 alkyl; R14 is hydrogen; R15 is hydrogen;with the proviso that R4 is different from hydrogen when

represents a group of formula

The term “alkyl”, as used herein, represents saturated, monovalenthydrocarbon radicals having straight (unbranched) or branched or cyclicor combinations thereof and containing 1-20 carbon atoms, preferably1-10 carbon atoms, more preferably 1-4 carbon atoms; most preferredalkyl groups have 1-3 carbon atoms. Alkyl moieties may optionally besubstituted by 1 to 5 substituents independently selected from the groupconsisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy,alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl or aryl. Usually alkylgroups, in the present case, are methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, 1-ethylpropyl, n-heptyl,2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl,2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino) methyl,(propionylamino) methyl, (benzoylamino) methyl, (4-chlorophenoxy)methyl, benzyl, 2-phenylethyl or 2-(methylthio) ethyl. Preferred alkylgroups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl,2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl, azidomethyl,(acetylamino) methyl, (propionylamino) methyl, (benzoylamino) methyl or2-(methylthio) ethyl. More preferred alkyl groups are methyl, ethyl,n-propyl, i-propyl, n-butyl, azidomethyl or trifluoromethyl. Mostpreferred alkyl groups are methyl or n-propyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8 carbon atoms, usually 3-6 carbon atoms derived from a saturatedcyclic hydrocarbon, which may be substituted by any suitable groupincluding but not limited to one or more moieties selected from groupsas described above for the alkyl groups. Preferred cycloalkyl groups arecyclopropyl and cyclohexyl.

The term “alkenyl” as used herein, represents straight, branched orcyclic unsaturated hydrocarbon radicals or combinations thereof havingat least one carbon-carbon double bond, containing 2-12 carbon atoms,preferably usually 2-4 carbon atoms. Alkenyl groups are being optionallysubstituted with any suitable group, including but not limited to one ormore moities selected from groups as described above for the alkylgroups. Usually an alkenyl group is ethenyl (vinyl) optionallysubstituted by 1 to 3 halogens. Preferred alkenyl group, in the presentcase, is 2,2-difluorovinyl.

The term “alkynyl” as used herein, represents straight, branched orcyclic hydrocarbon radicals or combinations thereof containing at leastone carbon-carbon triple bond, containing 2-12 carbon atoms, preferably2-6 carbon atoms, and being optionally substituted by any suitablegroup, including but not limited to one or more moities selected fromgroups as described above for the alkyl groups. Preferably an alkynylgroup is a halogenoalkynyl group (haloalkynyl group). Groups qualifiedby prefixes such as “s”, “i”, “t” and the like (e. g. “i-propyl”,“s-butyl”) are branched derivatives.

The term “aryl” as used herein, is defined as phenyl optionallysubstituted by 1 to 4 substituents independently selected from halogen,cyano, alkoxy, alkylthio, C1 3 alkyl or azido, preferably halogen orazido. Usually aryl groups, in the present case are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or3-azido-2,4,6-trifluorophenyl. Preferably, aryl groups are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferred arylgroups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cycloalkyl moiety as defined above, having atleast one O, S and/or N atom interrupting the carbocyclic ringstructure. Heterocyclic ring moities can be optionally substituted byalkyl groups or halogens and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Usuallyheterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl,1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl,4-chloro-1-methyl-1H-pyrazol-3-yl,5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl,3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl,4-methyl-1H-imidazol-5-yl, or 2-methyl-1,3-thiazol-4-yl. Preferredheterocycles are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl,1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrol-2-yl,1H-pyrrol-2-yl.

The term “halogen”, as used herein, includes an atom of chlorine,bromine, fluorine, iodine. Usually halogens are chlorine, bromine andfluorine. Preferred halogens are fluorine, bromine and chlorine.

The term “hydroxy”, as used herein, represents a group of formula—OH.

The term “alkoxy”, as used herein, represents a group of formula—ORawherein Ra is an alkyl group, as defined above. Preferred alkoxy groupis methoxy.

The term “aryloxy”, as used herein, represents a group of formula—ORbwherein Rb is an aryl group, as defined above. Preferred aryloxy groupis phenoxy.

The term “ester”, as used herein, represents a group of formula—COORCwherein Rc is an alkyl group or aryl group, as defined above. Preferredester group is methoxycarbonyl.

The term “amido”, as used herein, represents a group of formula—CONH2.

The term “amino”, as used herein, represents a group of formula—NH2.

The term “aminoderivative”, as used herein, represents an alkylamino oran arylamino group, wherein the terms “alkyl” and “aryl” are defined asabove.

The term “cyano”, as used herein, represents a group of formula—CN.

The term “nitro”, as used herein, represents a group of formula—N02.

The term “azido”, as used herein, represents a group of formula—N3.

The term “guanidine”, as used herein, represents a group offormula—NHC(═NH) NH2.

The term “alkylthio”, as used herein, represents a group of formula—SRdwherein

Rd is an alkyl group, as defined above. One alkylthio group ismethylthio.

The term “alkylsulfonyl”, as used herein, represents a group offormula—S(═O) 2Re wherein Re is an alkyl group, as defined above. Onealkylsulfonyl group is methylsulfonyl.

The term “alkylsulfinyl”, as used herein, represents a group offormula—S(═O) Rf wherein Rf is an alkyl group, as defined above. Onealkylsulfinyl group is methylsulfinyl.

The term “arylthio”, as used herein, represents a group of formula—SRgwherein Rg is an aryl group, as defined above.

The term “arylsulfonyl”, as used herein, represents a group of theformula—S(═O) 2Rh wherein Rh is an aryl group, as defined above.

The term “arylsulfinyl”, as used herein, represents a group of theformula—S(═O) Ri wherein Ri is an aryl group, as defined above.

The term “carbamate”, as used herein, represents a group offormula—N(H)C(O) OR1, wherein Ri is an alkyl or an aryl, as definedabove. Usually carbamate groups are (propoxycarbonyl) amino or(benzyloaxycarbonyl)amino. One carbamate group is (benzyloaxycarbonyl)amino.

The term “alkanoylamino”, as used herein, represents a group of theformula—NHC (═O) Rk wherein Rk is an alkyl group, as defined above.

The term “(arylcarbonyl) amino”, as used herein, represents a group ofthe formula—NHC(═O) Rm wherein Rm is an aryl group, as defined above.One (arylcarbonyl) amino is benzoylamino.

Usually, RI is hydrogen; Cl lo alkyl unsubstituted or substituted byhalogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy;C3-6 cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl groups; or guanidine.

In some embodiments, RI is hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl;2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl;2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio) ethyl; chloro; bromo;nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl;1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. More preferably, RI ishydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl; methylthio; nitro;cyano; amino; chloro or 1H-pyrrol-2-yl. Most preferably, RI is hydrogen;methyl; methylthio; nitro; cyano; amino or chloro.

Usually, R2 is hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-N-methyl)amino]carbonyl. Preferably, R2 ishydrogen; methyl; hydroxymethyl; (acetylamino) methyl; (propionylamino)methyl; (benzoylamino) methyl; [(benzyloxy) carbonyl]amino; chloro orcyano. In some embodiments, R2 is hydrogen; chloro or cyano.

Usually, R3 is hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano. In some embodiments, R3 is hydrogen;hydroxymethyl; chloro; cyano.

In some embodiments, R3 is hydrogen or cyano. In some embodiments R3 ishydrogen.

Usually, R4 is hydrogen; C1 4 alkyl unsubstituted or substituted byhalogens; C2 4 alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens. Preferably, R4 ishydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl;3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Morepreferably, R4 is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R4is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or3-azido-2,4-difluorophenyl.

Usually, R4a is hydrogen.

Usually, R5 is hydrogen.

Usually, R6 is hydrogen or C1-1-0 alkyl unsubstituted or substituted byhydroxy or azido. Preferably, R6 is hydrogen or azidomethyl. Morepreferably R6 is hydrogen. Usually R7 is hydrogen.

In other embodiments, R6 and R7 are linked to form a cyclopropyl.

In other embodiments, R2 and R3 can form together with the imidazolering the following 1H-benzimidaole cycle

Usually, R8 is hydrogen.

Usually, R9 is hydrogen; halogen; 1-3 alkyl or alkoxy. In someembodiments, R9 is hydrogen; methyl; chloro or methoxy. In someembodiments R9 is hydrogen.

Usually, RIO is hydrogen; halogen; cyano; C1 3 alkyl unsubstituted orsubstituted by halogens; or alkoxy. In some embodiments, RIO is methyl;hydrogen; trifluoromethyl; fluoro; cyano or methoxy. In some embodimentsR10 is hydrogen; trifluoromethyl; fluoro or cyano.

Usually, RI 1 is hydrogen.

In other embodiments, R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

Usually, R12 is hydrogen or halogen. In some embodiments R12 ishydrogen; chloro or fluoro. In some embodiments R12 is hydrogen.

Usually, R13 is hydrogen; C1 3 alkyl; halogen or thiazolyl unsubstitutedor substituted by alkyl groups, such as methylthiazolyl. In someembodiments R13 is hydrogen; chloro; bromo or methyl. In someembodiments R13 is chloro; bromo or methyl.

Usually R14 is hydrogen.

Usually, R15 is hydrogen.

In a general embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salts thereof, are those wherein

RI is selected from hydrogen; Cl lo alkyl unsubstituted or substitutedby halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C3 6cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl group; or guanidine; R2 is selected from hydrogen;C1-4 alkyl unsubstituted or substituted by hydroxy, alkanoylamino orbenzoylamino; halogen; ester; cyano; alkyl carbamate or[(N-methoxy-N-methyl)amino]carbonyl.R3 is selected from hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano; R4 is selected from hydrogen; C1 4alkyl unsubstituted or substituted by halogens; C2 4 alkenyl substitutedby halogens or phenyl group unsubstituted or substituted by azido or/andhalogens;R4a is hydrogen; R5 is hydrogen; R6 is selected from hydrogen or C1-10alkyl unsubstituted or substituted by hydroxy or azido;R7 is hydrogen; or R6 and R7 can be linked to form a cyclopropyl; or R2and R3 can form together with the imidazole ring the following1H-benzimidazole cycle

R8 is hydrogen; R9 is selected from hydrogen; halogen; C1-3 alkyl;alkoxy; R10 is selected from hydrogen; halogen; cyano or Cil alkylunsubstituted or substituted by halogens; or alkoxy; R1 is hydrogen; orR4, R4a and R5 can form together with the 2-oxo-1-pyrrolidine ring thefollowing 1,3-dihydro-2H-indol-2-one cycle

R12 is selected from hydrogen or halogen; R13 is selected from hydrogen;CI-3 alkyl; halogen; thiazolyl unsubstituted or substituted by alkylgroups, such as methylthiazolyl; R14 is hydrogen; R15 is hydrogen; withthe proviso that R4 is different from hydrogen when

represents a group of formula

In an embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl;2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl;hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chloro;bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl;1,2,3-thiadiazol-4-yl; or 1H-imidazol-2-yl; R2 is selected fromhydrogen; methyl; hydroxymethyl; (acetylamino) methyl; (propionylamino)methyl; (benzoylamino) methyl; (benzyloxycarbonyl) amino; chloro; orcyano; R3 is selected from hydrogen; hydroxymethyl; chloro; cyano; or R2and R3 can form together with the imidazole ring the following1H-benzimidazole cycle

R8 is hydrogen; R9 is selected from hydrogen; methyl; choro; methoxy;R10 is selected from methyl; hydrogen; trifluoromethyl; fluoro; cyano;or methoxy; R is hydrogen; R4 is selected from hydrogen; n-propyl;2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl;3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl; or 3-azido-2,4,6-trifluorophenyl. R4a ishydrogen; R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R12 is selected from hydrogen; chloro; fluoro; R13 is selected fromhydrogen; chloro; bromo; methyl; R14 is hydrogen; R15 hydrogen; R6 isselected from hydrogen; azidomethyl; R7 is hydrogen; or R6 and R7 arelinked to form a cyclopropyl; with the proviso that R4 is different fromhydrogen when

represents a group of formula

In one embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;n-butyl; methylthio; nitro; cyano; amino; chloro; or 1H-pyrrol-2-yl; R2is selected from hydrogen; chloro; cyano; R3 is selected from hydrogen;cyano; or R2 and R3 can form together with the imidazole ring thefollowing 1H-benzimidazole cycle

R8 is hydrogen; R9 is hydrogen;R10 is selected from hydrogen; trifluoromethyl; fluoro; cyano;RI 1 is hydrogen; R4 is selected from hydrogen; n-propyl;2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl;3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; or3-azido-2,4-difluorophenyl; R4a is hydrogen; R5 is hydrogen; or R4, R4aand R5 can form together with the 2-oxo-1-pyrrolidine ring the following1,3-dihydro-2H-indol-2-one cycle

wherein R12 is hydrogen; R13 is selected from methyl; chloro; bromo; R14is hydrogen; R15 hydrogen; R6 is hydrogen; R7 is hydrogen; with theproviso that R4 is different from hydrogen when

R11 represents a group of formula

In one embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; methylthio; nitro; cyano; amino;chloro; R2 is selected from hydrogen; chloro; cyano; R3 is hydrogen; R4is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl; R4a is hydrogen;R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R12 is hydrogen; R13 is selected from chloro; bromo; methyl; R14 ishydrogen; R15 hydrogen; R6 is hydrogen; R7 is hydrogen.

In some embodiments, compounds are: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;4-(3-azido-2,4,6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(IH-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(IH-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-IH-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-phenyl-1H-imidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmelthyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmelthyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;methyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylate;1-[(2-nitro-IH-imidazol-1-yl)methyll-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,4-dichloro-IH-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-ylmethyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5=trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-methyl}-1H-imidazole-5-carbonitrile;1-[(5-methyl-2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-IH-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,5-dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-IH-imidazol-1-yl)methyll-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(4-chloro-IH-imidazol-1-yl)methyll-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[4-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;benzyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-5-ylcarbamate;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide; N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide;N-1(1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrroldin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide;1-(IH-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;1-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(chloromethyl)-1H-benzimidazol-1-yl]melthyl}-4-propylpyrrolidin-2-one;{1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}acetonitrile;1-[(5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5,6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(6-chloro-IH-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[6-methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazole-5-carbonitrile;1-[(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-ylmethyl}-4-propylpyrrolidin-2-one;1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1,2,3-thiadiazol-4-yl)-1H-benzimidazole-5-carbonitrile;1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(1-ethylpropyl)-6-methoxy-IH-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-IH-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]melthyl}pyrrolidin-2-one;1-1[2-(3-furyl)-5-(trifluoromethyl)-IH-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-(IH-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile;and1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds are: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one, 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl) pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-1(5-chloro-IH-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(+1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+); 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds are:1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluoromethyl)-1-(IH-imidazol-1-ylmetliyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl) pyrrolidin-2-one;1-H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl) pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

Some compounds are:(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one.

The acid addition salt form of a compound of formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula I containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e. g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e. g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e. g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.,45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

Some of the compounds of formula I may also exist in tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

In another preferred embodiment, the present invention concerns alsocompounds of formula IA and their tautomeric form IB

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically. Compounds according to the presentinvention may exist in different polymorphic forms. Although notexplicitly indicated in the above formula, such forms are intended to beincluded within the scope of the present invention.

The invention also includes within its scope pro-drug forms of thecompounds of formula I and its various sub-scopes and sub-groups.

xii) U.S. Patent Application Publication No. 20090018148

In one aspect the invention provides compounds having formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

whereinR1 is hydrogen or C1-6 alkyl;R2 is hydrogen or C1-4 alkyl;R3 is a group of formula —CHR5R6 or a benzyl group;R4 is C1-8 alkyl optionally substituted by alkoxycarbonyl, C3-6cycloalkyl, aryl or heterocycle;R5 is C2-4 alkyl;R6 is C2-4 alkyl, amido or —COOR7;R7 is C1-4 alkyl;

In one aspect, the invention provides compounds:

When R1 is hydrogen, R2 is methyl, R3 is —CHR5R6, R6 is ethoxycarbonyland R5 is ethyl, then R4 is different from methyl, n-propyl, i-propyl,n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or2-phenylethyl;

When R1 is hydrogen, R2 is methyl, R3 is benzyl, then R4 is differentfrom i-propyl, n-butyl, 3-methylbutyl, benzyl, phenylethyl-, or3-phenylpropyl;

When R1 and R2 are methyl, R3 is benzyl, R4 is different from methyl,3-methylbutyl, benzyl, 3-phenylpropyl or 4-chlorophenylmethyl;

Finally8-(2-chloro-benzylsulfanyl)-3-methyl-7-octyl-3,7-dihydro-purine-2,6-dioneis considered.

Usually when R3 is a benzyl group, then R4 is C1-8 alkyl optionallysubstituted by alkoxycarbonyl.

Usually when R3 is a group of formula —CHR5R6, then R4 is C1-8 alkyloptionally substituted by C3-6 cycloalkyl, aryl or heterocycle.

The term “alkyl”, as used herein, is a group which represents saturated,monovalent hydrocarbon radicals having straight (unbranched) or branchedmoieties, or combinations thereof, and containing 1-8 carbon atoms,preferably 1-6 carbon atoms; more preferably alkyl groups have 1-4carbon atoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl orheterocycle. Alkyl moieties may be optionally substituted by acycloalkyl as defined hereafter. Preferred alkyl groups according to thepresent invention are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-butyl, i-butyl, n-pentyl, 3-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl or(5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl,cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl,n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or(5-nitro-2-furyl)methyl. Most preferred alkyl groups are methyl, ethyl,3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8, preferably 3 to 6 carbon atoms derived from a saturated cyclichydrocarbon, which may be substituted by any suitable group includingbut not limited to one or more moieties selected from groups asdescribed above for the alkyl groups. Preferred cycloalkyl groupaccording to the present invention is cyclohexyl.

The term “aryl” as used herein, is defined as a phenyl group optionallysubstituted by 1 to 4 substituents independently selected from halogen,amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl,3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

The term “phenyl”, as used herein, represents an aromatic hydrocarbongroup of formula —C6H5.

The term “benzyl group”, as used herein, represents a group of formula—CH2-aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groupsare benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or3-aminobenzyl. In some embodiments alkyl groups are 3-methoxybenzyl or3-nitrobenzyl.

The term “halogen”, as used herein, represents an atom of fluorine,chlorine, bromine, or iodine. In some embodiments the halogen isbromine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “amino”, as used herein, represents a group of formula —NH2.

The term “ethynyl”, as used herein, represents a group of formula —C≡CH.

The term “alkoxy”, as used herein, represents a group of formula —ORawherein

Ra is an alkyl group, as defined above. In some embodiments the alkoxygroup is methoxy.

The term “nitro”, as used herein, represents a group of formula —NO2.

The term “amido”, as used herein, represents a group of formula—C(═O)NH2.

The term “acyl”, as used herein, represents a group of formula —C(═O)Rbwherein Rb is an alkyl group, as defined here above. In some embodimentsthe acyl group is acetyl (—C(═O)Me).

The term “alkoxycarbonyl (or ester)”, as used herein, represents a groupof formula —COORc wherein Rc is an alkyl group; with the proviso that Rcdoes not represent an alkyl alpha-substituted by hydroxy. In someembodiments the alkoxycarbonyl group is ethoxycarbonyl.

The term “heterocycle”, as used herein, represents a 5-membered ringcontaining one or two heteroatoms selected from O or N. The heterocyclemay be substituted by one or two C1-4 alkyl or nitro. In someembodiments the heterocycles are (3,5-dimethylisoxazol-4-yl) or(5-nitro-2-furyl). Most preferred heterocycle is (5-nitro-2-furyl).

Generally R1 is hydrogen or C1-6 alkyl. Usually R1 is hydrogen or C1-6alkyl optionally substituted by hydroxy, alkoxy, cyano, ethynyl,alkoxycarbonyl or acyl. In some embodiments R1 is hydrogen, methyl,cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl,3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. In some embodiments R1is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl,3-hydroxypropyl or 2-propynyl. In some embodiments R1 is hydrogen.

Generally R2 is hydrogen or C1-4 alkyl. Usually R2 is hydrogen orunsubstituted C1-4 alkyl. In some embodiments R2 is hydrogen, methyl orn-butyl. In some embodiments, R2 is methyl.

Generally R3 is a group of formula —CHR5R6 or a benzyl group. In someembodiments R3 is 3-pentyl, 1-(aminocarbonyl)propyl,1-(ethoxycarbonyl)propyl or 3-bromobenzyl. In some embodiments R3 is1-(ethoxycarbonyl)propyl. Generally R4 is C1-8 alkyl optionallysubstituted by alkoxycarbonyl, C3-6 cycloalkyl, aryl or heterocycle.Usually R4 is C1-8 alkyl optionally substituted by cyclohexyl, phenyl,bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl,aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl orethoxycarbonyl. In some embodiments R4 is n-butyl, i-butyl, n-pentyl,n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl,4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl,4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl,(3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or1-(ethoxycarbonyl)propyl. In some embodiments R4 is n-butyl, n-hexyl,benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl,(3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or1-(ethoxycarbonyl)propyl. In some embodiments R4 is 3-methoxybenzyl,3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Generally R5 is C2-4 alkyl. Usually R5 is unsubstituted C2-4 alkyl. Insome embodiments R5 is ethyl.

Generally R6 is C2-4 alkyl, amido or —COOR7. Usually R6 is unsubstitutedC2-4 alkyl, amido or —COOR7. In some embodiments R6 is ethyl, amido orethoxycarbonyl. In some embodiments R6 is ethoxycarbonyl.

Generally R7 is C1-4 alkyl. Usually R7 is unsubstituted C1-4 alkyl. Insome embodiments, R7 is ethyl.

Usually the invention provides compounds having formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

whereinR1 is hydrogen, C1-6 alkyl optionally substituted by hydroxy, alkoxy,cyano, ethynyl, alkoxycarbonyl or acyl;R2 is hydrogen or unsubstituted C1-4 alkyl;R3 is a group of formula —CHR5R6 or a benzyl group;R4 is C1-8 alkyl optionally substituted by cyclohexyl, phenyl,bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl,aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl orethoxycarbonyl;R5 is unsubstituted C2-4 alkyl;R6 is unsubstituted C2-4 alkyl, amido or —COOR7;R7 is unsubstituted C1-4 alkyl;with the proviso that when R1 is hydrogen, R2 is methyl, R3 is —CHR5R6,R6 is ethoxycarbonyl and R5 is ethyl, then R4 is different fromn-propyl, i-propyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl,4-methylbenzyl or 2-phenylethyl.

In the above embodiment, sometimes, when R3 is a benzyl group, then R4is C1-8 alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, sometimes, when R3 is a group of formula—CHR5R6, then R4 is C1-8 alkyl optionally substituted by C3-6cycloalkyl, aryl or heterocycle.

In one embodiment,

R1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-pentyl or n-hexyl;R2 is hydrogen, methyl or n-butyl;R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;R4 is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;with the proviso that when R1 is hydrogen, R2 is methyl and R3 is1-(ethoxycarbonyl)propyl, then R4 is different from n-pentyl,3-bromobenzyl or 2-phenylethyl.

In the above embodiment, sometimes, when R3 is 3-bromobenzyl, then R4 isC1-8 alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, sometimes, when R3 is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R4 isdifferent from 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment, R1 is hydrogen, methyl, cyanomethyl,2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl;

R2 is methyl;R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;R4 is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;with the proviso that when R1 is hydrogen, R2 is methyl and R3 is1-(ethoxycarbonyl)propyl, then R4 is different from 3-bromobenzyl.

In the above embodiment, sometimes, when R3 is 3-bromobenzyl, then R4 is1-(ethoxycarbonyl)propyl;

In the above embodiment, sometimes, when R3 is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R4 isdifferent from 1-(ethoxycarbonyl)propyl;

In one embodiment, R1 is hydrogen; R2 is methyl; R3 is1-(ethoxycarbonyl)propyl; and R4 is 3-methoxybenzyl, 3-nitrobenzyl or(5-nitro-2-furyl)methyl.

A further embodiment consists in compounds wherein R2 is methyl, R3 is agroup of formula —CHR5R6 with R5 being C2-4 alkyl, R6 being amido or—COOR7 and R7 being methyl or ethyl.

In some embodiments, compounds are ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate;and ethyl2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments compounds are: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments compounds are: ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;and ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

The acid addition salt form of a compound of formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula I containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.,45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically. Compounds according to the presentinvention may exist in different polymorphic forms. Although notexplicitly indicated in the above formula, such forms are intended to beincluded within the scope of the present invention.

xiii) U.S. Pat. No. 7,465,549

In some embodiments, the compound includes optionally substitutedN-alkylated 2-oxo-pyrrolidine derivatives. In some embodiments, thosecompounds are alkyl amides derivatives substituted on the positions 4and/or 5 of the pyrrolidone ring.

Examples of optionally substituted N-alkylated 2-oxo-pyrrolidinederivatives include, but are not limited to, compounds such as(2S)-2-[(45)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide,(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide,(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide, and(2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide.

In some embodiments, the compounds further include optionallysubstituted N-alkylated 2-oxo-piperidinyl derivatives. In someembodiments, those compounds are alkyl amides derivatives substituted onthe position 4 and/or 5 and/or 6 of the 2-oxo-piperidinyl ring. Examplesof optionally substituted N-alkylated 2-oxo-pyrrolidine derivativesinclude, but are not limited to, compounds such as those referred to ininternational patent application PCT/EP02/05503 such as(2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,(2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, and(2S)-2-[4-(2-fluoro-2-methylpropyl)-2-oxo-1-pyrrolidinyl]butanamide.

In some embodiments, the compounds include any acetam compound offormula I, in racemic or isomeric form, or a pharmaceutically acceptablesalt thereof,

whereinR represents hydrogen or hydroxy;R1 and R2 represent independently hydrogen or an alkyl group of 1-4carbon atoms; andR3 and R4 represent independently hydrogen, an alkyl group of 1-4 carbonatoms or —(CH2)n-NR5R6 wherein n is 1, 2 or 3 and R5 and R6 representindependently hydrogen or an alkyl group of 1-4 carbon atoms.

An example of such an acetam compound includes, but is not limited to, acompound of formula I wherein R, R1, R2, R3 and R4 are hydrogen,2-oxo-pyrrolidineacetamide, known by the generic name piracetam asdescribed in UK Patents Nos. 1,039,113 and 1,309,692.

In some embodiments, the compounds also include optionally substitutedN-alkylated 2-oxo-azepanyl derivatives. Preferably, those compounds arealkyl amides derivatives substituted on the positions 4 and/or 5 and/or6 and/or 7 of the 2-oxo-azepanyl ring. Examples of optionallysubstituted N-alkylated 2-oxo-azepanyl derivatives include, but are notlimited to, compounds such as those referred to in international patentapplication PCT/EP02/05503 such as2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

xiv) U.S. Patent Application Publication No. 2006258704

This invention provides novel compounds of the formula I

whereinn represents 0 or 1 whereby R<1> is not existent when n=0 and R<1> isexistent when n=1;A<1> represents an oxygen or a sulfur atom;X is —CONR<7> R<8>, —COOR<9>, —CO—R<10> or CN; R<1> when existent, R<2>,R<3>, R<4> and R<5> are the same or different and each is independentlyhydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido,carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl,ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative,amino derivative, acyl derivative, sulfonyl derivative or sulfinylderivative,provided that at least one of the substituents R chosen from R<1> whenexistent, R<2>, R<3>, R<4> or R<5> is not hydrogen;R<6> is hydrogen, alkyl, aryl or —CH2-R<6a> wherein R<6a> is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;R<7>, R<8> and R<9> are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; andR<10> is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle ora thio derivative;their pharmaceutically acceptable salts, geometrical Isomers (includingcis and trans, Z and E isomers), enantiomers, diastereoisomers andmixtures thereof(including all possible mixtures of stereoisomers).

In the above formula, at least one substituent R<1> to R<5> is differentfrom hydrogen. Some non-substituted compounds are referred to in U.S.Pat. Nos. 5,468,733 and 5,516,759. U.S. Pat. No. 5,468,733 disclosesnon-ring substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinylderivatives as inhibitors of the oncogene Ras protein. In particular,these compounds block the ability of Ras to transform normal cells tocancer cells, and therefore can be included in several chemotherapeuticcompositions for treating cancer.

U.S. Pat. No. 5,516,759 discloses non-ring substituted2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivativespresent at the N-terminus of dodecapeptides possessing LHRH (luteinizinghormone-releasing hormone) antagonistic activity. Such LHRH antagonistsare useful in the treatment of a variety of conditions in whichsuppression of sex steroids plays a key role including contraception,delay of puberty, treatment of benign prostatic hyperplasia a.o.

In the definitions set forth below, unless otherwise stated, R<11> andR<12> are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein, is defined as including—O—R<11> groups wherein R<11> is as defined above except for “oxyderivative”. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy,acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy,arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxysuch as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy,2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative”, as used herein, is defined as including—S—R<11> groups wherein R<11> is as defined above except for “thioderivative”. Non-limiting examples are alkylthio, alkenylthio,alkynylthio and arylthio.

The term “amino derivative”, as used herein, is defined as including—NHR<11> or —NR<11> R<12> groups wherein R<11> and R<12> are as definedabove. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl-and arylamino or mixed amino.

The term “acyl derivative”, as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R<11> —CO—, wherein R<11> is as defined above and may also behydrogen. Preferred are acyl derivatives of formula —COR<11> whereinR<11> is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12alkenyl, heterocyle and aryl. Non-limiting examples are formyl, acetyl,propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl,cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl,furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl,oxamoyl.

The term “sulfonyl derivative”, as used herein, is defined as includinga group of the formula —SO—R<11>, wherein R<11> is as defined aboveexcept for “sulfonyl derivative”. Non-limiting examples arealkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative”, as used herein, is defined as includinga group of the formula —SO—R<11>, wherein R<11> is as defined aboveexcept for “sulfinyl derivative”. Non-limiting examples arealkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and generally containing 1-20 carbonatoms, most often 1 to 12 carbon atoms, preferably 1-7 carbon atoms fornon-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these twopreferred cases, unless otherwise specified, “lower alkyl”), eachoptionally substituted by, preferably 1 to 5, substituents independentlyselected from the group consisting of halogen, hydroxy, thiol, amino,nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinylderivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl,sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester,oxyamido, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy(preferably C6-10) and aryl(preferably C6-10).

In some embodiments are alkyl groups containing 1 to 7 carbon atoms,each optionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio,cyclopropyl, acyl and phenyl. Most preferred are C1-4 alkyl and C3-7cycloalkyl, each optionally substituted by one or more hydroxy, halogen,lower alkyl or/and azido.

In some embodiments are alkyl groups are hydroxymethyl, propyl, butyl,2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl,2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to C1 to C7 saturated straight, branched or cyclic hydrocarbon.Non limiting examples are methyl, ethyl, propyl, isopropyl, butyl,tertiobutyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl,hexyl, isohexyl, cyclohexyl, 3-methypentyl, 2,2-dimethylbutyl,optionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferably, lower alkyl is methyl.

The term “alkenyl”, as used herein, is defined as including bothbranched and unbranched, unsaturated hydrocarbon radicals having atleast one double bond, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro,cyano, aryl and heterocycle.

In some embodiments are alkenyl groups are C2-C12 alkenyls, especiallyC2-6alkenyls, such as ethenyl (=vinyl), 1-methyl-1-ethenyl,2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl,2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl,3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl and the like, optionally beingsubstituted by one or more substituents selected from halogen, cyano,thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl. Mostpreferred is vinyl, optionally substituted by one or more halogen or/andlower alkyl, and especially 2,2-difluorovinyl, 2,2-dibromovinyl and2,2-dichlorovinyl.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido,alkylthio, alkyl and acyl.

In some embodiments are alkynyl groups are C2-12 alkynyl, especiallyC2-6 alkynyl, optionally being substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, acyl, arylsuch as phenyl and alkyl, preferably cycloalkyl.

In some embodiments are ethynyl, propynyl and butynyl, optionallysubstituted by lower alkyl or/and halogen, and especially 1-propynyl,cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e.g. “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of at least onering, most often 1 to 3 rings and generally containing 6-30 carbon atomsby removal of one hydrogen, such as phenyl and naphthyl, each optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonicacid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio,oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl,C1-6-haloalkyl. Aryl radicals are preferably monocyclic or bicycliccontaining 6-10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl each optionally substituted by one or more substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkyl, C1-6-haloalkyl, sulfonyl and phenyl. In some embodiments thearyl is phenyl, optionally substituted by one or more halogen, loweralkyl, azido or nitro, such as 3-chlorophenyl and 3-azidophenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO2.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO2.

The term “amino”, as used herein, represents a group of the formula—NH2.

The term “azido”, as used herein, represents a group of the formula —N3.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO3H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO2NH2.

The term “ester”, as used herein, is defined as including a group offormula —COO—R<11> wherein R<11> is as defined above except oxyderivative, thio derivative or amino derivative. Preferred are esters offormula —COOR<11> wherein R<11> is selected from C1-12 alkyl, C2-12alkenyl, C2-12 alkynyl and aryl. Most preferred are esters where R<11>is a lower alkyl, especially methyl.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH2 or—CONHR<11> or —CONR<11> R<12> wherein R<11> r and R<12> are as definedabove.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl, and optionallybeing substituted with any suitable group, including but not limited toone or more moieties selected from lower alkyl, or other groups asdescribed above for the alkyl groups. Non-limiting examples ofheterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl,triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl,benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl,benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl,1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenothiazinyl, furazanyl, benzodioxolyl, isochromanyl,indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl,2-oxo-pyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose,ribose, fructose, which may also be substituted) optionally substitutedby alkyl or as described above for the alkyl groups. The term“heterocycle” also includes bicyclic, tricyclic and tetracyclic, spirogroups in which any of the above heterocyclic rings is fused to one ortwo rings independently selected from an aryl ring, a cyclohexane ring,a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or anothermonocyclic heterocyclic ring or where a monocyclic heterocyclic group isbridged by an alkylene group, such as quinuclidinyl,7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl,8-azabicyclo(3.2.1)octanyl.

The heterocycle may be selected from triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyland piperazinyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino,acyl and phenyl. In some embodiments the heterocycle is selected fromtetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl andthienyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, halogen substituted alkyl, acyl, alkoxy,nitro, amino and phenyl, and especially from 2- and 3-thienyl,optionally substituted by one or more halogen, acyl such as formyl,cyano and/or lower alkyl, such as methyl.

In the above definitions it is to be understood that when a substituentsuch as R<1>, R<2>, R<3>, R<4>, R<5>, R<7>, R<8>, R<9>, R<10> isattached to the rest of the molecule via a heteroatom or a carbonyl, astraight- or branched chain, C1-12-, preferably C1-4-alkylene or C2-12,preferably C2-4-alkenylene or -alkynylene bridge may optionally beinterposed between the heteroatom or the carbonyl and the point ofattachment to the rest of the molecule.

The acid addition salt form of a compound of formula (I) that occurs inits free form as a base can be obtained by treating said free base formwith an appropriate acid such as an inorganic acid, for example, ahydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric,phosphoric and the like; or an organic acid, such as, for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic,maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt form,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.(1976), 45, 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

Furthermore, certain compounds of formula I which contain alkenyl groupsmay exist as Z (zusammen) or E (entgegen) isomers. In each instance, theinvention includes both mixture and separate individual isomers.

Multiple substituents on the piperidinyl or the azepanyl ring can alsostand in either cis or trans relationship to each other with respect tothe plane of the piperidinyl or the azepanyl ring.

Some of the compounds of formula I may also exist in tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof unless the particular isomeric formis referred to specifically. The invention also includes within itsscope prodrug forms of the compounds of formula I and Its varioussub-scopes and sub-groups.

The term “prodrug” as used herein includes compound forms which arerapidly transformed in vivo to the parent compound according to theinvention, for example, by hydrolysis in blood. Prodrugs are compoundsbearing groups which are modified by biotransformation prior toexhibiting their pharmacological action. Such groups include moietieswhich are readily oxidised, cyclised or cleaved, which compound afterbiotransformation remains or becomes pharmacologically active. Forexample, metabolically cleavable groups form a class of groups wellknown to practitioners of the art. They include, but are not limited tosuch groups as alkanoyl (i.e. acetyl, propionyl, butyryl, and the like),unsubstituted and substituted carbocyclic aroyl (such as benzoyl,substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl (such asethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethylsilyl),monoesters formed with dicarboxylic acids (such as succinyl), phosphate,sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compoundsbearing the biotransformable groups have the advantage that they mayexhibit improved bioavailability as a result of enhanced solubilityand/or rate of absorption conferred upon the parent compound by virtueof the presence of the biotransformable group. T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery System”, Vol. 14 of the A.C.S. SymposiumSeries; “Bioreversible Carriers in Drug Design”, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987.

The term “R substituent” refers to R<1>, R<2>, R<3>, R<4> or R<5>,independently.

According to one embodiment, the present invention relates to a compoundof formula I as defined above wherein n represents 0. The compound is a6-ring structure (2-thioxo- or 2-oxo-piperidinyl derivative) whereinR<1> is not existent since n=0, and is depicted by the formula (I-A).

According to a following embodiment, the present invention relates to acompound of formula I according to the invention as defined abovewherein n represents 1. The compound is a 7-ring structure (2-thioxo- or2-oxo-azepanyl derivative) wherein R<1> is existent since n=1 anddepicted by the formula (I-B).

According to one embodiment, the invention relates to said compound asdefined above wherein n=0, R<3> and/or R<4> are different from hydrogenand R<2> and R<5> represent hydrogen.

According to another embodiment, the invention relates to said compoundas defined above wherein n=1, R<2>, R<3> and/or R<4> are different fromhydrogen and wherein R<1> and R<5> represent hydrogen.

According to another embodiment, the invention relates to said compoundas defined above wherein only one R substituent chosen from R<3> or R<4>when n=0 or from R<2>, R<3> or R<4> when n=1, is different from hydrogenand the remaining R substituent(s) is/are hydrogen. We hereby refer to amono-substituted 2-thioxo- or 2-oxo-piperidinyl or 2-thioxo- or2-oxo-azepanyl derivatives. According to another embodiment, the presentinvention relates to compounds of formula I according to the inventionas defined above wherein A<1> represents an oxygen atom. We hereby referto 2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein X is CONR<7> R<8>, especially CONH2. We hereby refer to amidoderivatives of 2-oxo(or thioxo)-piperidinyl or 2-oxo(orthioxo)-azepanyl.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein R<6> represents hydrogen, C1-4 alkyl, or a CH2-R<6a> groupwherein R<6a> represents a heterocycle. Most preferably R<6> is a C1-4alkyl, especially ethyl. When R<6> is ethyl we refer to 2-(2-oxo(orthioxo)-1-piperidinyl)butanamide or 2-(2-oxo(orthioxo)-1-azepanyl)butanamide derivatives.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein the carbon atom to which R<6> is attached is of the Sconfiguration. In case where R<6> is ethyl, A is oxygen and X is CONR<7> R<8>, we refer then to (2S)-2-(2-oxo-1-piperidinyl)butanamide or(2S)-2-(2-oxo-1-azepanyl)butanamide derivatives. According to oneembodiment, the present invention relates to a compound as defined abovewherein R<2> when n=1, R<3> and R<4> are the same or different and eachis independently hydrogen, halogen, nitro, nitrooxy, cyano, carboxy,amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester,ether, aryl, heterocycle, acyl derivative, sulfonyl derivative orsulfinyl derivative:

R<1> when existent, R<2> when n=0 and R<5> are hydrogen;R<6> is hydrogen, alkyl, aryl or —CH2-R<6a> wherein R<6a> is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;provided that, when R<6> is hydrogen, X is —CONR<7> R<8> and that thecompound isneither methyl (2R)-2-[(6R)-6-methyl-2-oxoazepanyl]-3-phenylpropanoatenor methyl (2S)-2-[(4R)-4-methyl-2-oxoazepanyl]-3-phenylpropanoate.

According to this embodiment, the compound is generally such that whenR<6> is benzyl, X is —COOCH3 and n=1, R<2> is different from methyl whenR<3> and R<4> are both hydrogen and R<4> is different from methyl whenR<2> and R<3> are both hydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein R<2> when n=1, R<3> and R<4> are thesame or different and each is independently hydrogen; cyano; carboxy;amido;

C1-12 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cycloalkyl, acyl, aryl and heterocycle;C2-12 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl;C2-12 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl; acyl derivative of formula —CO—R<11>, wherein R<11> isselected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle andaryl;ester of formula —CO—O—R<11> wherein R<11> is selected from C1-12 alkyl,C2-12 alkenyl, C2-12 alkynyl and aryl;heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl,each optionally substituted by one or more substituents selected fromhalogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl andphenyl;aryl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino,azido, sulfonyl, aryl and nitro.

According to another embodiment, the present invention relates to acompound as defined above, wherein R<2> when n=1, R<3> and R<4> are thesame or different and each is independently hydrogen;

C1-7 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cyclopropyl, acyl and phenyl;C2-6 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl:C2-6 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl: heterocycle selected from tetrazolyl, pyrrolidinyl,pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionallysubstituted by one or more substituents selected from halogen, alkyl,halogen substituted alkyl, acyl, alkoxy, nitro, amino and phenyl;phenyl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, halogen substituted alkyl, halogen, alkoxy, amino,azido, sulfonyl, phenyl and nitro.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently C1-4-alkyl orC3-7-cycloalkyl, optionally substituted by one or more halogen, hydroxy,lower alkyl and/or azido.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently vinyl, optionallysubstituted by one or more halogen or/and lower alkyl.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the group R3and R<4> when n=0, represents independently ethynyl, propynyl orbutynyl, optionally substituted by one or more halogen and/or loweralkyl.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently phenyl, optionallysubstituted by one or more halogen, lower alkyl, azido and/or nitro.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently 2- or 3-thienyl,optionally substituted by one or more halogen, acyl, cyano or/and loweralkyl.

According to a particular embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<3>, R<4> and R<2> when n=1 or from the groupR<3> and R<4> when n=0, is hydroxymethyl, propyl, butyl,3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl,3-azidophenyl, 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl,2-ethynyl, 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl,3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl,1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl,2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl,2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to yet another embodiment, the present invention relates to acompound as defined above wherein R<1>, R<2>, R<4> and R<5> arehydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein R<1>, R<2>, R<3> and R<5> arehydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein n=1 and R<1>, R<3>, R<4> and R<5> arehydrogen.

In all the above-mentioned scopes when the carbon atom to which R<6> isattached is asymmetric it may be in the “S”-configuration.

Representative compounds of this invention as defined above are selectedfrom the group consisting of2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-propyl-1-piperidinyl)butanamide,2-12-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo 1-piperidinyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-propyl-1-piperidinyl)butanamide,2-[2-oxo-4-(3,3,3-trifluoroproyl)-1-piperidinyl]butanamide,2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(iodomethyl)-2-oxo-1-piperldinyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,2-12-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-5-propyl-1-azepanyl)butanamide,2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-(5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-5-phenyl-1-azepanyl)butanamide,2-[2-oxo-5-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide,2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-azepanyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-6-propyl-1-azepanyl)butanamide,2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-16-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-6-phenyl-1-azepanyl)butanamide,2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide,2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(4-methyl-2-thienyl]-2-oxo-1-azepanyl]butanamide,2-[2-oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide,2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-4-propyl-1-azepanyl)butanamide,2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-[4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-4-phenyl-1-azepanyl)butanamide,2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[<4>-(5-cyano-<2>-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl]-2-oxo-1-azepanyl]butanamide,2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

Results have been obtained with the following compounds:

-   (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,-   (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

xv) International Patent Application Publication No. WO2008/132139

In some embodiments, the compounds are of formula (I) as follows:

whereinY is O or S. In some embodiments Y is O. R1 is hydrogen or C-|.g alkyl;R2 is hydrogen;R3 is —CONR5R6, —COR7, an imidazolyl, an imidazopyridinyl, animidazopyridazinyl; R5, R6 are the same or different and areindependently selected from hydrogen and C-|_(—)6 alkyl;R7 is C<;|_(—)6 alkyl;A is a monocyclic or bicyclic heterocyclic moiety selected from thegroup consisting of imidazolidin-1-yl, 1,3-oxazolidin-3-yl,2,5-dihydro-1H-pyrrol-1-yl, 1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl,piperidin-1-yl, azepan-1-yl, 5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl; R4 is either R̂a or R̂b dependingon whether A being is a monocyclic or a bicyclic heterocycle:where A is a monocyclic heterocyclic moiety, R̂ is R̂a which is selectedfrom the group consisting of hydrogen; C-|.g alkyl optionallysubstituted by a substituent selected from halogen, C-1.4 alkoxy, C-1.4alkylthio, azido, nitrooxy or an aryl;C2-6 alkenyl optionally substituted by halogen; C2-6 alkynyl optionallysubstituted by halogen; azido; alkoxycarbonylamino; arylsulfonyloxy; asubstituted or unsubstituted aryl; or a 3-8 membered substituted orunsubstituted heterocycle;where A is a bicyclic heterocyclic moiety R̂ is R̂ which is selected fromthe group comprising or consisting of hydrogen; nitro; cyano; halogen;heterocycle; amino; aryl; C-|.g alkyl optionally substituted by at leastone halogen; or C-|.g alkoxy optionally substituted by at least onehalogen;

In some embodiments the compounds are as follows:

For compounds where A=Y is selected from a 2-oxo-piperidin-1-yl, a2-oxo-azepan-1-yl, a 2-oxo-1,3-benzothiazol-3(2H)-yl or a2-oxo-1,3-benzoxazol-3(2H)-yl, R3 must be selected from an imidazolyl,an imidazopyridinyl or an imidazopyridazinyl.

For compounds where A=Y is a 5-oxoimidazolidin-1-yl, R̂ and R̂ arehydrogen, R3 is —CONR5R6, R5 and R6 are as above defined, then R̂a maynot be an alkyl, aralkyl or substituted aralkyl.

Where A=Y is either of a 2-oxo-piperidin-1-yl and a 2-oxo-azepan-1-yl,R̂, R̂ and R̂a are all hydrogen, then R̂ could not be a2-phenylimidazo[1,2-a]pyridin-3-yl.

In a specific embodiment A=Y is selected from the list consisting of:

wherein X is O or S, in a more specific embodiment O; in anotherembodiment, X is S.

The asterisks in the above illustration indicate the attachment sites ofthe substituent R̂a.

In a specific embodiment, when R̂ is —CONR5R6 and R̂ is C-μg alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

In a specific embodiment R̂ is hydrogen, methyl, ethyl and R̂ is hydrogen.In a specific embodiment R3 is —CONH2.

In a further specific embodiment R̂ is 1H-imidazol-1-yl,1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl orimidazo[1,2-b]pyridazin-3-yl. In a specific embodiment R̂a is a C-|.galkyl which may optionally be substituted by a halogen; or a phenyl.

In another specific embodiment R̂b is hydrogen, halogen, nitro, cyano ora C-μg alkyl optionally substituted by a halogen.

In still a further embodiment compounds may be used in the treatment ofthe above mentioned disorders, in particular of epilepsy, having theformula (I-E), as wells as its geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

wherein

X is O or S;

R-I is hydrogen or C-|.g alkyl, in a more specific embodiment hydrogen;R3 is an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl; R̂b ishydrogen; nitro; cyano; halogen; C-|.g alkyl optionally substituted byhalogen; C-|.g alkoxy optionally substituted by halogen.

A further aspect of the present invention consists in novel compoundshaving the formula (I-A), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

whereinR1 is hydrogen or C-|.g alkyl, preferably hydrogen, methyl or ethyl; ina more specific embodiment R̂ is ethyl.R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl,preferably R̂ is —CONH2.R̂a is either hydrogen or an aryl; with the proviso that2-(5-oxoimidazolidin-1-yl)acetamide is excluded. Preferably R̂a is anaryl, e.g. a phenyl which may be substituted preferably by halogen,nitro, alkoxy, in particular by nitro.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and R̂ are attached is preferably in the“S”-configuration. A further aspect of the present invention consists innovel compounds having the formula (I-B1 or I-B2), their geometricalisomers, enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

wherein X in formula (I-B2) is either S or O, in a more specificembodiment S; R1 is hydrogen or C-|.g alkyl, preferably hydrogen, methylor ethyl; in a more specific embodiment R̂ is ethyl.R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;preferably R̂ is —CONH2R̂a is hydrogen; C-|.g alkyl optionally substituted by halogen or C-1.4alkoxy; an aryl; or C2.g alkenyl optionally substituted by halogen.Preferably, R̂a is C-|.g alkyl optionally substituted by halogen or C2-6alkenyl optionally substituted by halogen or an aryl. In a more specificembodiment R̂a is C-|.g alkyl optionally substituted by halogen or aryl.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration. A further aspect of the present invention consists innovel compounds having the formula (I-B3), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

whereinR1 is either hydrogen or C-μg alkyl, preferably hydrogen, methyl orethyl; more preferably R1 is ethyl.R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;preferably R̂ is —CONH2 R̂a is C-|_(—)5 alkyl optionally substituted byhalogen or C-1.4 alkoxy; an aryl; or C2_g alkenyl optionally substitutedby halogen. Preferably, R̂a is C-|.g alkyl optionally substituted byhalogen or C2_g alkenyl optionally substituted by halogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration. A further aspect of the present invention consists innovel compounds having the formula (I-C), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

whereinR1 is hydrogen or C-|.g alkyl, in particular hydrogen, methyl or ethyl.R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;in particular R̂ is —CONH2R̂a is methyl, ethyl, butyl optionally substituted by halogen or C-1.4alkoxy, an unsubstituted phenyl or a phenyl substituted by halogen, aC-|.g alkyl optionally substituted by halogen or a C-1.4 alkoxy; or R̂ais a C2-6 alkenyl optionally substituted by halogen. Preferably, R̂a ismethyl, optionally substituted by halogen, an unsubstituted phenyl or aphenyl substituted by halogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and Rβ are attached is preferably in the“S”-configuration. A further aspect of the present invention consists incompounds having the formula (I-D1 or I-D2), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

whereinR—I is hydrogen or C-|.g alkyl, in particular hydrogen; R3 is animidazolyl, an imidazopyridinyl or an imidazopyridazinyl. In oneembodiment, R̂ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl. In a morespecific embodiment, R̂ is 1H-imidazol-1-yl, 1H-imidazol-4-yl,1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl;R̂a is hydrogen, C-|.g alkyl optionally substituted by halogen or C-1.4alkoxy; aryl; or C2-g alkenyl optionally substituted by halogen. In aspecific embodiment, R̂a is C-|.g alkyl optionally substituted byhalogen; aryl; or C2-6 alkenyl optionally substituted by halogen. In amore specific embodiment R̂a is C-|.g alkyl optionally substituted byhalogen; or aryl; e.g., propyl or phenyl;with the proviso that when R̂ and R̂a are hydrogen, R̂ is not2-phenylimidazo[1,2-a]pyridin-3-yl.

A further aspect of the present invention consists in compounds havingthe formula (I-F1, I-F2 or I-F3), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

whereinR-I is hydrogen or C-|.g alkyl, preferably hydrogen, methyl or ethyl;more preferably, R̂ is hydrogen.R3 is —CONH2, an imidazolyl, an imidazopyridinyl or animidazopyridazinyl; in a more specific embodiment R3 is —CONH2,1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl. R̂b ishydrogen; halogen; nitro; cyano; C1.4 alkyl optionally substituted byhalogen; C-1.4 alkoxy optionally substituted by halogen. In a morespecific embodiment R̂ is hydrogen, halogen or cyano, more specificallyhalogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and Rβ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in compounds havingthe formula (I-F4), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

whereinR-I is hydrogen or C-|.g alkyl, preferably hydrogen;R3 is an imidazolyl, an imidazopyridinyl or an imidazopyridazinyl; morespecifically R̂ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl. Morespecifically R̂ is 1H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl.R̂b is hydrogen; halogen; nitro; cyano; C-1.4 alkyl optionallysubstituted by halogen; C-1.4 alkoxy optionally substituted by halogen;specifically R̂ is hydrogen, halogen or cyano.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in compounds havingeither of the formula (I-G1, I-G2 or I-G3), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

whereinR-I is hydrogen or C-|.g alkyl; preferably hydrogen;R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;in a more specific embodiment R̂ is —CONH2, 1H-imidazol-1-yl,1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl orimidazo[1,2-b]pyridazin-3-yl. In a even more specific embodiment R3 isan 1H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl;R4D is hydrogen; halogen; C-1.4 alkyl optionally substituted by halogen;C-1.4 alkoxy optionally substituted by halogen.

Specific compounds of the present invention are those selected from thegroup consisting of:(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide;2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piperidin-2-one;1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one;5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one;1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one;4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one;1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one;1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one;2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide;5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one;2-(6-iodo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;2-(6-cyano-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one;and7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

In some embodiments, compounds of the present invention are thoseselected from the group consisting of:1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; and5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification andembodiments unless an otherwise expressly set out definition provides abroader definition.

“C-|_β alkyl” refers to alkyl groups having 1 to 6, or 1 to 4 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,trifluoromethyl and the like. “Aryl” refers to an unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferredaryl include phenyl, naphthyl, phenantrenyl and the like.

“Heterocycle” refers to a saturated or unsaturated ring systemcontaining, in addition to carbon atoms, at least one hetero atom, suchas nitrogen, oxygen and/or sulfur. “Heterocycle” includes both“heteroaryl” and “heterocycloalkyl”.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl,1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazopyridinyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl, benzoquinolyl, imidazopyrimidinyl, imidazopyridazinyl,imidazothiazolyl or imidazothiadiazolyl.

“C2-6 alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (vinyl, —CH═CH2), n-2-propenyl(allyl, —CH2CH═CH2) and the like.

“C2-6 alkynyl” refers to alkynyl groups preferably having from 2 to 6carbon atoms and having at least 1-2 sites of alkynyl unsaturation,preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH2C≡CH),and the like.

“C3.8 cycloalkyl” refers to a saturated carbocyclic group of from 3 to 8carbon atoms having a single ring (e.g., cyclohexyl) or multiplecondensed rings (e.g., norbornyl). Preferred cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and thelike.

“Heterocycloalkyl” refers to a C3.8 cycloalkyl group according to thedefinition above, in which 1 to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined ashydrogen or C-|.g alkyl.

“Alkoxy” refers to the group —O—R where R includes “C-μg alkyl”, “C2-6alkenyl”,

“C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”,“heteroaryl”.

“Amino” refers to the group —NRR′ where each R, R′ is independentlyhydrogen,

“C-|.g alkyl”, “C2-6 alkenyl”, “C2-6 alkynyl”, “C3-8 cycloalkyl”,

“heterocycloalkyl”, “aryl”, “heteroaryl”, and where R and R′, togetherwith the nitrogen atom to which they are attached, can optionally form a3-8-membered heterocycloalkyl ring.

“Amido” refers to the group —C(═O)NRR′ where each R, R′ is independentlyhydrogen, “C-|_(—)5 alkyl”, “C2-6 alkenyl”, “C2-6 alkynyl”, “C3.8cycloalkyl”, “heterocycloalkyl”, “aryl”,

“heteroaryl”, and where R and R′, together with the nitrogen atom towhich they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“Acylamino” refers to the group —NRC(O)R′ wherein R and R′ are asdefined hereabove for the amino group.

“Ureido” refers to the group —NR¹¹C(O)NRR′ wherein R and R′ are asdefined hereabove for the amino group, and R¹¹ is as defined hereabove.“Sulfanyl” refers to the group —SR where R is “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Sulfinyl” refers to the group —S(═O)R where R is “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Sulfonyl” refers to the group —S(═O)2R where R is “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and

“heteroaryl” etc. groups can optionally be substituted with from 1 to 5substituents selected from the group consisting of “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”,“cycloalkyl”, “heterocycloalkyl”, “amino”, “amido”, “acylamino”,“ureido”, “aryl”, “heteroaryl”, “alkoxy”, “halogen”, cyano, hydroxy,mercapto, nitro, “amido”, “sulfanyl”, “sulfinyl”, “sulfonyl” and thelike.

The acid addition salt form of a compound of formula (I) that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula (I) and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula (I) and some of their intermediateshave at least one stereogenic center in their structure. Thisstereogenic center may be present in a R or a S configuration, said Rand S notation is used in correspondence with the rules described inPure Appl. Chem., 45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula (I)or mixtures thereof (including all possible mixtures of stereoisomers).With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

Some of the compounds of formula (I) may also exist in tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

The invention also includes within its scope pro-drug forms of thecompounds of formula (I) and its various sub-scopes and sub-groups.

In a specific embodiment, the present invention concerns a compoundselected from the group consisting of:(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide;2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;(+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piperidin-2-one;1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one;5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-5-phenylazepan-2-one;5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one;1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one;4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one;1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(2-OXO-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;6-bromo-3-(2-oxopropyl)-1,3-benzothiazol-2(3H)-one;2-(6-nitro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one;1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one;2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide;5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;2-(6-bromo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one;2-(6-iodo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;2-(6-cyano-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one;and7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

xvi) UK Patent 1,039,113

The new compounds according to the present invention are N-substitutedlactams of the general formula:

wherein N is a whole number of from 3 to 5 and R represents a

radical in which m is 0, 1 or 2 and R′ is a hydrogen atom or an alkyl,cycloalkyl, alkenyl or alkynyl radical, which may contain 3 to 6 carbonatoms, or an aryl radical, and R″ is a hydrogen atom or an alkylradical, or both R′ and R″, together with the nitrogen atom to whichthey are attached, form a heterocyclic ring, such as 5 a pyrrolidinering.

xvii) UK Patent 1,309,692

According to the present invention, there are provided new N-substitutedlactams of the general formula:

wherein X is a hydrogen atom or an alkyl, alkenyl or alkynyl radicalcontaining 1 to 6 carbon atoms, p is a whole number of from 1 to 6, Y isa hydrogen atom or an alkyl, alkenyl or alkynyl radical containing 1 to6 carbon atoms or a cycloalkyl radical and R′ and R″, which may be thesame or different, are hydrogen atoms or alkyl, alkenyl, alkynyl,cycloalkyl or aryl radicals or R′ and R″, together with the nitrogenatom to which they are attached, form a heterocyclic radical which maycontain further heteroatoms, with the proviso that at least one of thesymbols X and Y is other than a hydrogen atom.

Antipsychotics

The antipsychotics suitable for use in the present invention may be anyantipsychotic drugs or agents or pharmaceutically acceptable salts,hydrates, solvates, polymorphs or prodrugs thereof

(1) “Typical” and “Atypical” Antipsychotics

Among the antipsychotics or pharmaceutically acceptable salts, hydrates,solvates, polymorphs and prodrugs thereof that are useful in the methodsand compositions of this invention are atypical and typicalantipsychotics.

In some embodiments, the antipsychotic is an atypical antipsychotic orpharmaceutically acceptable salts, hydrates, solvates, prodrugs andpolymorphs thereof. Atypical antipsychotics offer several clinicalbenefits including, for example, superior side effect profiles,particularly with regard to extrapyramidal side effects (EPS). Atypicalantipsychotics typically differ from typical antipsychotics in their“limbic-specific” dopamine type 2 (D2)-receptor binding. Atypicalantipsychotics, also display a high ratio of serotonin type 2(5-HT2)-receptor binding to D2 binding. Atypical antipsychotics havehigh affinity for the 5-HT2-receptor and function as antagonists ofserotonin for the 5-HT2-receptor.

Examples of atypical antipsychotics include, but are not limited to:Aripiprazole,7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-di-hydrocarbostyril(commercially available from Bristol-Meyers Squibb Co., Princeton, N.J.under the trade name Ability®) is disclosed in U.S. Pat. Nos. 4,734,416and 5,006,528, which are incorporated herein by reference. Exemplaryformulations and dosages of aripiprazole suitable for use in treatingschizophrenia and bipolar disorder are described in U.S. Pat. Nos.6,977,257; 7,115,587; and 7,550445, which are herein incorporated byreference in their entirety. Asenapine,trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole(under trade name Saphris® or Sycrest®) is disclosed in U.S. Pat. Nos.4,145,434 and 5,763,476, which are herein incorporated by reference intheir entirety. An orthorhombic crystal form of asenapine is describedin U.S. Pat. No. 7,741,358, which is also incorporated herein byreference. Clozapine,8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine(commercially available from Mylan Pharmaceuticals, Morgantown, W. Va.under the trade name Mylan®) is disclosed in U.S. Pat. No. 3,539,573,which is herein incorporated by reference. Clinical efficacy ofClozapine in the treatment of schizophrenia has previously beendisclosed. Hanes, et al., Psychopharmacol. Bull., 24, 62 (1988).

Iloperidone,1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone(under trade name Fanapt®) is disclosed in EP Patent EP402644, which isincorporated herein by reference. The use of iloperidone in treatingpsychotic symptom and exemplary dosages of iloperidone suitable for suchtreatment are disclosed in U.S. Pat. USRE39198, which is incorporatedherein by reference.

Olanzapine,2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,disclosed in U.S. Pat. No. 5,229,382 (commercially available from EliLilly, Indianapolis, Ind. under the trade name Zyprexa®) which is herebyincorporated by reference, as being useful for the treatment ofschizophrenia, schizophreniform disorder, acute mania, mild anxietystates, and psychosis. The use of olanzapine in treating schizophreniaand exemplary dosages of olanzapine for such use are disclosed in U.S.Pat. Nos. 5,625,897, 5,627,178, 5,817,655, 5,919,485 and 6,960,577.Olanzapine polymorphs are disclosed in U.S. Pat. No. 5,736,541,incorporated herein by reference. Olanzapine hydrate forms are disclosedin U.S. Pat. No. 6,251,895, incorporated herein by reference.Lurasidone,(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-yl-methyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione(developed by Dainippon Sumitomo Pharma Co., Ltd. under trade nameLatuda®) is disclosed in U.S. Pat. No. 5,532,372, incorporated herein byreference. Paliperidone,3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4Hpyrido[1,2-a]pyrimidin-4-one(developed by Janssen Pharmaceutica under the trade name Invega® orInvega Sustenna®), is disclosed in EP Patent 368388. The use ofpaliperidone in treating psychosis and exemplary formulations for suchuse are disclosed in U.S. Pat. Nos. 5,158,952,5,254,556,5,352459,6,077,843 and 6,555,544, all of which areincorporated herein by reference.

Quetiapine,5-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)-eth-oxy]ethanol(commercially available from Astra Zeneca, Wilmington, Del. under thetradename Seroquel®) its activity in assays which demonstrate utility inthe treatment of schizophrenia are disclosed in U.S. Pat. No. 4,879,288,which is herein incorporated by reference. Exemplary formulations ofquetiapine for use in treating schizophrenia and bipolar disorder aredisclosed in U.S. Pat. No. 5,948,437, incorporated herein by reference.

Risperidone,3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one(commercially available from Janssen under the trade name Risperdal®)and its use in the treatment of psychotic diseases are disclosed in U.S.Pat. No. 4,804,663, which is herein incorporated by reference.

Sertindole,1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]imidazolidin-2-one,is described in U.S. Pat. No. 4,710,500.

Its use in the treatment of schizophrenia is described in U.S. Pat. Nos.5,112,838 and 5,238,945. U.S. Pat. Nos. 4,710,500; 5,112,838; and5,238,945 are herein incorporated by reference in their entirety.

Ziprasidone,5-[2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one,(commercially available from Pfizer Inc., New York, N.Y. under the tradename Geodon®) is disclosed in U.S. Pat. Nos. 4,831,031 and 5,312,925 andits activity in assays which demonstrate utility in the treatment ofschizophrenia are described in U.S. Pat. No. 4,831,031, all of which areherein incorporated by reference.

Surmontil (trimipramine maleate),5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz (b,f) azepineacid maleate (Commercially available from Odyssey Pharmaceuticals, Inc.,North Hanover, N.J. under the trade name Surmotil®).

In some embodiment, the antipsychotic for the methods and compositionsof this invention is selected from aripiprazole, olanzapine andziprasidone, or pharmaceutically acceptable salts, hydrates, solvates,polymorphs or prodrugs thereof.

In some embodiments of the invention, the antipsychotic is a typicalantipsychotic. Such typical antipsychotics include, but are not limitedto, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine,chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine,droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol,heptaminol, isopropamide iodide, levomepromazine, levosulpiride,loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine,penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone,pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl,pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine,thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine,trihexyphenidyl, and zuclopenthixol, and pharmaceutically acceptablesalts, hydrates, solvates, prodrugs and polymorphs thereof.

(2) Antipsychotics Displaying Various Pharmacology/Mechanisms

Suitable antipsychotics or pharmaceutically acceptable salts, hydrates,solvates, polymorphs, or prodrugs thereof for the present invention maybe selected from compounds/agents that are dopaminergic agents,glutamatergic agents, NMDA receptor positive allosteric modulators,glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropicglutamate receptors (mGluRs) agonists or positive allosteric modulators(PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5positive allosteric modulators (PAMs), M1 muscarinic acetylcholinereceptor (mAChR) positive allosteric modulators (PAMs), histamine H3receptor antagonists, AMPA/kainate receptor antagonists, ampakines(CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,nNOS inhibits, neurosteroids, and neurotrophic factors.

In some embodiments, the antipsychotic is a dopaminergic agent selectedfrom dopamine D1 receptor antagonists or agonists (for example,dihydrexidine, A77636 and SKF81297), dopamine D₂ receptor antagonists orpartial agonists (e.g., some typical and atypical antipsychotics),dopamine D3 receptor antagonists or agonists (for example, S33084,SB-277011-A, AVE5997 and (±)-PD128907), dopamine D4 receptor antagonists(for examples, clozapine and sonepiprazole (U-101387 or PNU-101387G)).

In some embodiments, the antipsychotic is a glutamatergic agent selectedfrom NMDA receptor positive allosteric modulators (e.g., glycine,D-cycloserine and D-serine), glycine reuptake inhibitors (e.g.,N-(3-(4′-fluorophenyl)-3-(4′-phenylphenoxyl)propyl) sarcosine andglycyldodecylamide), glutamate reuptake inhibitor (e.g., excitatoryamino-acid transporters EAAT3 antagonists), metabotropic glutamatereceptors agonists (e.g., LY-354740), AMPA/kainate receptor antagonists(e.g., LY-293558, GYKI52466 and LY-326325), ampakines (CX-516), andglutathione prodrugs.

In some embodiments, the antipsychotic is a noradrenergic agent selectedfrom alpha-2 adrenergic receptor agonists or antagonists (e.g.,guanfacine, clozapine and risperidone) and COMT inhibitors (e.g.,tolcapone).

In some embodiments, the antipsychotic is a serotonin receptor modulatorselected from 5-HT_(2A) receptor antagonists, 5-HT_(1A) receptor partialagonists, 5-HT₂c agonists, and 5-HT6 antagonists (e.g., some atypicalantipsychotics).

In some embodiments, the antipsychotic is a cholinergic agent selectedfrom alpha-7 nicotinic receptor agonists (e.g.,3-2,4-dimethoxybenzylidene anabaseine (DMXB-A or GTS-21)), alpha4-beta2nicotinic receptor agonists (e.g., SIB-1553A), allosteric modulators ofnicotinic receptors and acetylcholinesterase inhibitors, muscarinicreceptor agonists and antagonists (e.g., N-desmethylclozapine,xanomeline, PTAC, and BuTAC).

In some embodiments, the antipsychotic is selected from cannabinoid CB1antagonists (e.g., SR141716), neurokinin 3 antagonists (e.g., osanetant(SR-142801) and talnetant), neurotensin agonists (e.g., SR-48692), MAO Binhibitors (e.g., Selegiline (deprenyl) and rasagiline), PDE10inhibitors (e.g., Papaverine), NNOS inhibits (e.g., methylene blue,LNOARG, L-NAME, and 7-nitroindazole), neurosteroids (e.g.,dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S),pregnenolone (PREG) and pregnenolone sulfate (PREGS)), and neurotrophicfactors (e.g., nerve growth factor (NGF), brain-derived neurotrophicfactor (BDNF) and neurotrophin (NT)-3/4/5)).

(3) Antipsychotics Useful for Treating Symptoms of Schizophrenia orBipolar Disorder (in Particular, Mania)

In some embodiments, the antipsychotics or pharmaceutically acceptablesalts, hydrates, solvates, polymorphs and prodrugs thereof that areuseful in the methods and compositions of this invention include thosethat are useful in treating one or more signs or symptoms ofschizophrenia or bipolar disorder (in particular, mania).

Schizophrenia is characterized by psychological symptoms such asperception (hallucinations), ideation, reality testing (delusions),thought processes (loose associations), feeling (flatness, inappropriateeffect), behavior (catatonia, disorganization), attention,concentration, motivation (avolition, impaired intentions and planning)and judgment (see for example Diagnostic and Statistical Manual ofMental Disorders IV, American Psychiatric Association). In general, thesymptoms of schizophrenia are divided into positive and negativesymptoms with hallucinations and delusions being positive features, andfeatures such as flatness, poverty of speech and impaired executivefunctions representing negative symptoms. Clinical rating scales such asPositive and Negative Syndrome Scale and Scale for the Assessment ofNegative Symptoms provide criteria to differentiate between, and rate,positive and negative symptoms. Frequently included in the descriptionof negative symptoms are the cognitive deficits schizophrenic andschizotypical patients suffer from. These include impairment inattention, verbal fluency, executive functions such as planning, workingmemory and visual and verbal learning and memory. These types ofcognitive dysfunction can be measured with a variety of tests, such asVisual Search, Verbal Fluency, Wisconsin Card Sorting, Trail Making—PartB, Symbol Digit, Hopkins Verbal Learning, Digit Span, Stroop-Color-Wordand Attentional Capacity. MATRICS consensus neuropsychological testbattery which includes tests of working memory, speed of processing,attention, verbal learning, visual learning, reasoning and problemsolving and social cognition. Moreover, it has been found that cognitivemeasures predict work function and overall outcome as assessed by theGlobal Assessment Scale and Quality of Life Scale. Several studies havenow demonstrated that neuropsychological functions, reflecting severalnegative and cognitive symptoms of the disease, may be more impaired inmale schizophrenic patients when compared to female patients. Further,there are a number of other psychiatric diseases such as schizotypicaland schizoaffective disorder, other acute- and chronic psychoses andbipolar disorder which have an overlapping symptomatology withschizophrenia. Any compounds or pharmaceutically acceptable salts,hydrates, solvates, polymorphs and prodrugs thereof that are useful intreating at least one of the signs or symptoms of schizophrenia orbipolar disorder (in particular, mania), including, for example, thoserecited above, are useful in the methods and compositions of thisinvention.

Among the antipsychotics or pharmaceutically acceptable salts, hydrates,solvates, polymorphs and prodrugs thereof that are useful in the methodsand compositions of this invention are those disclosed, for example, inU.S. Pat. Nos. 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573;5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and5,312,925, and EP Patents EP402644 and EP368388, and thepharmaceutically acceptable salts, hydrates, solvates, polymorphs andprodrugs thereof

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Method of Treating Schizophrenia or Bipolar Disorder (in Particular,Mania) with the Administration of an SV2A Inhibitor and an Antipsychoticor Pharmaceutically Acceptable Salts Thereof

In one aspect, the invention provides methods for treating a subjectsuffering from schizophrenia or bipolar disorder (in particular, mania),or at risk thereof, by administering an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in combination with an antipsychotic or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof. In some embodiments, the methods of this inventiontreat one or more positive and/or negative symptoms, as well ascognitive impairment, associated with schizophrenia In some embodiments,the methods of this invention treat one or more symptoms, as well ascognitive impairment, associated with bipolar disorder (in particular,mania)..

The SV2A inhibitor and the antipsychotic suitable for the method of thisinvention may be selected from any of those as described above. In someembodiments, the SV2A inhibitor is selected from any of those describedabove; and the antipsychotic is selected from (1) atypical and typicalantipsychotics (such as those described above); (2) agents that aredopaminergic agents (such as dopamine D1 receptor antagonists oragonists, dopamine D₂ receptor antagonists or partial agonists, dopamineD3 receptor antagonists or partial agonists, dopamine D4 receptorantagonists), glutamatergic agents, NMDA receptor positive allostericmodulators, glycine reuptake inhibitors, glutamate reuptake inhibitor,metabotropic glutamate receptors (mGluRs) agonists or positiveallosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs),glutamate receptor glur5 positive allosteric modulators (PAMs), M1muscarinic acetylcholine receptor (mAChR) positive allosteric modulators(PAMs), histamine H3 receptor antagonists, AMPA/kainate receptorantagonists, ampakines (CX-516), glutathione prodrugs, noradrenergicagents (such as alpha-2 adrenergic receptor agonists or antagonists andCOMT inhibitors), serotonin receptor modulators (such as 5-HT_(2A)receptor antagonists, 5-HT_(1A) receptor partial agonists, 5-HT_(2C)agonists, and 5-HT6 antagonists), cholinergic agents (such as alpha-7nicotinic receptor agonists, alpha4-beta2 nicotinic receptor agonists,allosteric modulators of nicotinic receptors and acetylcholinesteraseinhibitors, muscarinic receptor agonists and antagonists), cannabinoidCB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO Binhibitors, PDE10 inhibitors, nNOS inhibits, neurosteroids, andneurotrophic factors, including, e.g., those specific such agents asdescribed above, and (3) any compounds that are useful in treating oneor more sign or symptoms of schizophrenia or bipolar disorder (inparticular, mania) (including, e.g., the agents disclosed in any of theabove-listed patents or patent application publications), andpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs thereof. In some embodiments, the SV2A inhibitor is selectedfrom the group consisting of levetiracetam, seletracetam, andbrivaracetam or derivatives or analogs or pharmaceutically acceptablesalts, or solvates, or hydrates, or polymorphs, or prodrugs thereof andthe antipsychotic is an atyptical antipsychotic selected from, e.g.,aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. Insome embodiments, the SV2A inhibitor is selected from levetiracetam orderivatives or analogs or pharmaceutically acceptable salts, orsolvates, or hydrates, or polymorphs, or prodrugs thereof and theantipsychotic is an atyptical antipsychotic selected from, e.g.,aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.

In some embodiments, the subject that suffers schizophrenia or bipolardisorder (in particular, mania) is a human patient. The subject may be ahuman or other mammal such as a non-human primate, or rodent (e.g.,rat). In some embodiments, the subject is a human patient.

In some embodiments, the use of the SV2A inhibitors and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs and prodrugs thereof incombination with antipsychotics and their pharmaceutically acceptablesalts, hydrates, solvates, polymorphs and prodrugs may reduce the amountof antipsychotics necessary for the treatment of schizophrenia orbipolar disorder (in particular, mania). In some embodiments, thesubject that suffers schizophrenia or bipolar disorder (in particular,mania) is a human patient, and thus the use of the SV2A inhibitorsreduce the side effects caused by antipsychotics without diminishingefficacy. Further, in some embodiments, the efficacy of a combination ofthe SV2A inhibitors and antipsychotics and pharmaceutically acceptablesalts, solvates, hydrates, polymorphs, and prodrugs thereof exceeds theefficacy of either drug administered alone at its optimal dose and thus,is an improved treatment for schizophrenia or bipolar disorder (inparticular, mania).

It will be appreciated that compounds and agents used in thecompositions and methods of this invention preferably should readilypenetrate the blood-brain barrier when peripherally administered.Compounds which cannot penetrate the blood-brain barrier, however, canstill be effectively administered directly into the central nervoussystem, e.g., by an intraventricular or other neuro-compatible routes.

As used herein, administration of SV2A inhibitor and an antipsychotic orpharmaceutically acceptable salts, hydrates, solvates, polymorphs andprodrugs thereof “in combination” includes simultaneous administrationand/or administration at different times, such as sequentialadministration. Simultaneous administration of the SV2A inhibitor andthe antipsychotic or their pharmaceutically acceptable salts, hydrates,solvates, polymorphs and prodrugs can optionally be combined withsupplemental doses of the SV2A inhibitor and/or the antipsychotic andtheir salts, hydrates, solvates, polymorphs and prodrugs. Simultaneousadministration of drugs encompasses administration as co-formulation or,alternatively, as separate compositions.

In accordance with this invention, the SV2A inhibitor and the psychotic,and pharmaceutically acceptable salts, solvates, hydrates, polymorphsthereof, can be administered to a subject via any suitable route orroutes. In some embodiments, the drugs are administered orally; however,administration intravenously, subcutaneously, intra-arterially,intramuscularly, intraspinally, rectally, intrathoracically,intraperitoneally, intracentricularly, or transdermally, topically, orby inhalation is also contemplated. The agents can be administeredorally, for example, in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, or the like, prepared by art recognizedprocedures. In certain embodiments, the SV2A inhibitor and theantipsychotic, and pharmaceutically acceptable salts, solvates,hydrates, polymorphs thereof, can be administered to a subject viadifferent routes. For example, the SV2A inhibitor or its salt, solvate,hydrate, or polymorph is administered intravenously and theantipsychotic or its salt, solvate, hydrate, or polymorph isadministered orally.

In some embodiments, the administration is a slow or extended release.The term “extended release” is widely recognized in the art ofpharmaceutical sciences and is used herein to refer to a controlledrelease of an active compound or agent from a dosage form to anenvironment over (throughout or during) an extended period of time, e.g.greater than or equal to one hour. An extended release dosage form willrelease drug at substantially constant rate over an extended period oftime or a substantially constant amount of drug will be releasedincrementally over an extended period of time. The term “extendedrelease” used herein includes the terms “controlled release,” “prolongedrelease,” “sustained release,” “delayed release,” or “slow release” asthese terms are used in the pharmaceutical sciences. In someembodiments, the extended release dosage is administered in the form ofa patch or a pump. The term “extended release form”, as used herein, mayrefer to a dosage form that contains one or more active ingredients,where the release of at least one of the active ingredient, when placedin water or other biological fluids or solvents, may occur over anextended period, such as a period of at least about 1 day, at leastabout 2 days, at least about 3 days, at least about 4 days, at leastabout 5 days, at least about 10 days, at least about 20 days, at leastabout 30 days, at least about 60 days, at least about 90 days, or atleast about 150 days.

As used herein, “immediate release formulation” refers to a formulationof an active pharmaceutical ingredient that releases greater than 80percent of the active pharmaceutical ingredient in less than one hour ina USP dissolution method known in the art or by the manufacturer for acommercial product. Typically, the release of the active ingredient inan immediate release formulation is greater than 80 percent in less than30 minutes.

When a solid carrier is used for administration, the preparation may bein a tablet, placed in a hard gelatin capsule in powder or pellet form,or it may be in the form of a troche or lozenge. If a liquid carrier isused, the preparation may be in the forms of a syrup, emulsion, softgelatin capsule, or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

Dosage schedules of the agents and compositions according to the methodsof the invention will vary according to the particular compound orcompositions selected, the route of administration, the nature of thecondition being treated, the age, and condition of the patient, thecourse, or stage of treatment, and will ultimately be at the discretionof the attending physician. It will be understood that the amount of theSV2A inhibitor and the antipsychotic and their pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs and prodrugs thereofadministered will be amounts effective to produce a desired biologicaleffect, such as beneficial results, including clinical results. It willbe understood that an effective amount can be administered in more thanone dose and over a course of treatment.

Desired duration of administration of the SV2A inhibitor and theantipsychotic and their pharmaceutically acceptable salts, hydrates,solvates, polymorphs and prodrugs thereof can be determined by routineexperimentation by one skilled in the art. For example, the SV2Ainhibitor and the antipsychotic and their pharmaceutically acceptablesalts, hydrates, solvates, polymorphs and prodrugs thereof may beadministered for a period of 1-4 weeks, 1-3 months, 3-6 months, 6-12months, 1-2 years, or more, up to the lifetime of the patient.

It is known in the art that normalization to body surface area is anappropriate method for extrapolating doses between species. The humanequivalent dose (HED) for this dosage can be estimated using thefollowing formula that accounts for differences in body surface area(see Estimating the Safe Starting Dose in Clinical Trials forTherapeutics in Adult Healthy Volunteers, December 2002, Center forBiologics Evaluation and Research):

HED=animal dose×(Km animal/Km human)

where the Km factor is body weight divided by body surface area (Km rathas been determined as 6, and Km human is 37; see Reagan-Saw, Nihal,Ahmad, 2007). Thus, a dosage of 10 mg/kg in rats is equivalent to 1.6mg/kg in humans (10 mg/kg×(6/37)=1.6 mg/kg). For human subjects, tocalculate a dose in mg from the dose in mg/kg, the dose in mg/kg ismultiplied by a typical adult weight of 70 kg.

The HED calculation is based on body surface area. As a result, it is anestimate of what human dose corresponds to an animal (e.g., rat) dose inthe context of a maximum safe starting dose for clinical trials inhumans. Calculating the HED is typically an initial step in carrying outthe clinical trial of a drug in humans. It is not an indication of theultimate human therapeutic dose. See, “Estimating the Safe Starting Dosein Clinical Trials for Therapeutics in Adult Health Volunteers, December2002, Center for Biologics Evaluation and Research.” Blood/plasma levelsare a far better predictor of therapeutic dose correspondence betweenanimals (e.g., rats) and humans.

In certain embodiments of the invention, the dose of the SV2A inhibitoror its pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug is 0.1 to 5 mg/kg/day (which, given a typical human subject of70 kg, is 7 to 350 mg/day).

In certain embodiments of the invention, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, andprodrugs thereof can be administered at doses according to, for example,United States (U.S.) patent application Ser. No. 12/580,464 (Pub. No.US-2010-0099735), U.S. patent application Ser. No. 13/287,531 (Pub. No.US-2012-0046336), U.S. patent application Ser. No. 13/370,253 (Pub. No.US-2012-0214859), International Patent Application PCT/US2009/005647(Pub. No. WO2010/044878), International Patent ApplicationPCT/US12/24556 (Pub. No. WO2012/109491), U.S. Patent Application61/105,847, U.S. Patent Application 61/152,631, U.S. Patent Application61/175,536, and U.S. Patent Application 61/441,251. In certainembodiments of the invention, the SV2A inhibitor or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, and prodrugs thereof isadministered every 12 or 24 hours at a daily dose of about 0.001 mg/kgto 5 mg/kg. In some embodiments, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, andprodrugs thereof is administered every 12 or 24 hours at a daily dose ofabout 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0.2 mg/kg,or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg, orabout 0.06 to 1.8 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1mg/kg, or about 0.5 to 5 mg/kg, or about 0.05 to 0.5 mg/kg. In certainembodiments of the invention, the SV2A inhibitor or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered every 12 or 24 hours at a daily dose of about 0.001 to 5mg/kg, about 0.001 to 0.5 mg/kg, about 0.01 to 0.5 mg/kg, about 0.1 to 5mg/kg, or about 1 to 2 mg/kg, or about 2 to 4 mg/kg, or about 2 to 3mg/kg, or about 3 to 4 mg/kg, or about 0.2 to 0.4 mg/kg, or about 0.2 to0.3 mg/kg, or about 0.3 to 0.4 mg/kg, or about 0.1 to 0.2 mg/kg, orabout 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.5 to 2 mg/kg, or about 0.8to 1.6, or about 0.8 to 3.6, or about 0.5 to 4 mg/kg, or about 0.04 to2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.05 to 3 mg/kg or about0.08 to about 1.6 mg/kg, or about 0.08 to 3.6 or about 0.05 to 2 mg/kg,or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.5 to 5mg/kg, or about 0.05 to 0.5 mg/kg, or about 0.8 mg/kg, or about 1.6mg/kg, or about 3.6 mg/kg, or about 0.08 mg/kg, or about 0.16 mg/kg, orabout 0.36 mg/kg. Other doses higher than, intermediate to, or less thanthese doses may also be used and may be determined by one skilled in theart following the methods of this invention. For repeatedadministrations over several days or weeks or longer, depending on thecondition, the treatment is sustained until a sufficient level ofcognitive function is achieved.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.001-5 mg/kg/day (which, given a typical human subject of 70 kg, isabout 0.07-350 mg/day). Doses that may be used include, but are notlimited to 0.001 mg/kg/day, 0.0015 mg/kg/day, 0.002 mg/kg/day, 0.005mg/kg/day, 0.0075 mg/kg/day, 0.01 mg/kg/day, 0.015 mg/kg/day, 0.02mg/kg/day, 0.03 mg/kg/day, 0.04 mg/kg/day, 0.05 mg/kg/day, 0.1mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day,0.75 mg/kg/day, 1.0 mg/kg/day, 1.5 mg/kg/day, 2.0 mg/kg/day, 2.5mg/kg/day, 3.0 mg/kg/day, 4.0 mg/kg/day, or 5.0 mg/kg/day. In someembodiments, the dose of the SV2A inhibitor is 0.001-0.5 mg/kg/day(which, given a typical human subject of 70 kg, is about 0.07-35mg/day), or 0.01-0.5 mg/kg/day (which is about 0.7-35 mg/day). Otherdoses higher than, intermediate to, or less than these doses may also beused and may be determined by one skilled in the art following themethods of this invention.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.1 to 5 mg/kg/day (which, given a typical human subject of 70 kg, is7 to 350 mg/day). Doses that may be used include, but are not limited to0.1 mg/kg/day, 0.5 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day, 2 mg/kg/day,2.5 mg/kg/day, 3 mg/kg/day, 4 mg/kg/day, or 5 mg/kg/day. In certainembodiments, the dose is 1-2 mg/kg/day (which, given a typical humansubject of 70 kg, is 70-140 mg/day). In other embodiments of theinvention, the dose of the SV2A inhibitor is 0.1 to 0.2 mg/kg/day. Otherdoses higher than, intermediate to, or less than these doses may also beused and may be determined by one skilled in the art following themethods of this invention.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.01 to 2.5 mg/kg/day (which, given a typical human subject of 70 kg,is about 0.7-180 mg/day). Doses that may be used include, but are notlimited to 0.01 mg/kg/day, 0.02 mg/kg/day, 0.03 mg/kg/day, 0.04mg/kg/day, 0.06 mg/kg/day, 0.08 mg/kg/day, 0.12 mg/kg/day, 0.14mg/kg/day, 0.16 mg/kg/day, 0.18 mg/kg/day, 0.2 mg/kg/day, 0.4 mg/kg/day,0.6 mg/kg/day, 0.8 mg/kg/day, 1.0 mg/kg/day, 1.2 mg/kg/day, 1.4mg/kg/day, 1.6 mg/kg/day, 1.8 mg/kg/day, 2.0 mg/kg/day, 2.2 mg/kg/day,2.4 mg/kg/day, or 2.5 mg/kg/day. In some embodiments, the dose of theSV2A inhibitor is 0.1-2.5 mg/kg/day (which, given a typical humansubject of 70 kg, is about 7-180 mg/day), 0.1-0.2 mg/kg/day (which isabout 7-15 mg/day), 0.2-0.4 mg/kg/day (about 14-30 mg/day), 0.4-2.5mg/kg/day (about 25-180 mg/day), 0.6-1.8 mg/kg/day (about 40-130mg/day), 0.04-2.5 mg/kg/day (about 2.5-180 mg/day) or 0.06-1.8 mg/kg/day(about 4-130 mg/day). In some embodiments of the invention, the dose ofthe SV2A inhibitor is 40 to 130 mg, 140 to 300 mg, 200 to 300 mg or 140to 200 mg. Other doses higher than, intermediate to, or less than thesedoses may also be used and may be determined by one skilled in the artfollowing the methods of this invention.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.0015 to 7 mg/kg/day (which, given a typical human subject of 70 kg,is about 0.1-500 mg/day). Daily doses that may be used include, but arenot limited to 0.0015 mg/kg, 0.002 mg/kg, 0.0025 mg/kg, 0.005 mg/kg,0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg,0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg,1.2 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, 2.2mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.5 mg/kg,4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 6.0 mg/kg, or 7.0 mg/kg; or 0.1 mg,0.15 mg, 0.18 mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg, 2.8 mg, 3.0mg, 3.5 mg, 4.2 mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12mg, 15 mg, 20 mg, 25 mg, 28 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120mg, 125 mg, 140 mg, 150 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210mg, 225 mg, 250 mg, 280 mg, 300 mg, 350 mg, 400 mg, or 500 mg. In someembodiments, the daily dose of SV2A inhibitor that can be used in themethods of this invention include, without limitation, 0.0015-5 mg/kg(or 0.1-350 mg for a subject of 70 kg), 0.01-0.8 mg/kg, 0.01-1 mg/kg,0.01-1.5 mg/kg, 0.01-2 mg/kg, 0.01-2.5 mg/kg, 0.01-3 mg/kg, 0.01-3.5mg/kg, 0.01-4 mg/kg, 0.01-5 mg/kg, 0.025-0.8 mg/kg, 0.025-1 mg/kg,0.025-1.5 mg/kg, 0.025-2 mg/kg, 0.025-2.5 mg/kg, 0.025-3 mg/kg,0.025-3.5 mg/kg, 0.025-4 mg/kg, 0.05-0.8 mg/kg, 0.05-1 mg/kg, 0.05-1.5mg/kg, 0.05-2 mg/kg, 0.05-2.5 mg/kg, 0.05-3 mg/kg, 0.05-3.5 mg/kg,0.05-4 mg/kg, 0.075-0.8 mg/kg, 0.075-1 mg/kg, 0.075-1.5 mg/kg, 0.075-2mg/kg, 0.075-2.5 mg/kg, 0.075-3 mg/kg, 0.075-3.5 mg/kg, 0.075-4 mg/kg,0.1-0.8 mg/kg, 0.1-1 mg/kg, 0.1-1.5 mg/kg, 0.1-2 mg/kg, 0.1-2.5 mg/kg,0.1-3 mg/kg, 0.1-3.5 mg/kg, 0.1-4 mg/kg, 0.2-0.8 mg/kg, 0.2-1 mg/kg,0.2-1.5 mg/kg, 0.2-2 mg/kg, 0.2-2.5 mg/kg, 0.2-3 mg/kg, 0.2-3.5 mg/kg,0.2-4 mg/kg, 0.5-0.8 mg/kg, 0.5-1 mg/kg, 0.5-1.5 mg/kg, 0.5-2 mg/kg,0.5-2.5 mg/kg, 0.5-3 mg/kg, 0.5-3.5 mg/kg, or 0.5-4 mg/kg; or 0.7-50 mg,0.7-75 mg, 0.7-100 mg, 0.7-150 mg, 0.7-180 mg, 0.7-225 mg, 0.7-250 mg,0.7-280 mg, 1.8-50 mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg, 1.8-180 mg,1.8-225 mg, 1.8-250 mg, 1.8-280 mg, 3.5-50 mg, 3.5-75 mg, 3.5-100 mg,3.5-150 mg, 3.5-180 mg, 3.5-225 mg, 3.5-250 mg, 3.5-280 mg, 5-50 mg,5-75 mg, 5-100 mg, 5-150 mg, 5-180 mg, 5-225 mg, 5-250 mg, 5-280 mg,7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg, 7-180 mg, 7-225 mg, 7-250 mg,7-280 mg, 15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg, 15-225mg, 15-250 mg, 15-280 mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150 mg,35-180 mg, 35-225 mg, 35-250 mg, or 35-280 mg. Other doses higher than,intermediate to, or less than these doses may also be used and may bedetermined by one skilled in the art following the methods of thisinvention.

In certain embodiments of the invention, the interval of administrationis 12 or 24 hours. Administration at less frequent intervals, such asonce every 6 hours, may also be used. In some embodiments, the SV2Ainhibitor is administered every 12 or 24 hours at a total daily dose of0.1 to 5 mg/kg (e.g., in the case of administration every 12 hours of adaily dose of 2 mg/kg, each administration is 1 mg/kg). In someembodiments, the SV2A inhibitor is administered every 24 hours at adaily dose of 1 to 2 mg/kg. In another embodiment, the SV2A inhibitor isadministered every 24 hours at a daily dose of 0.1-0.2 mg/kg. In someembodiments, the SV2A inhibitor is administered every 12 or 24 hours ata daily dose of 0.01 to 2.5 mg/kg (e.g., in the case of administrationevery 12 hours of a daily dose of 0.8 mg/kg, each administration is 0.4mg/kg). In some embodiments, the SV2A inhibitor is administered every 12or 24 hours at a daily dose of 0.1 to 2.5 mg/kg. In some embodiments,the SV2A inhibitor is administered every 12 or 24 hours at a daily doseof 0.4 to 2.5 mg/kg. In some embodiments, the SV2A inhibitor isadministered every 12 or 24 hours at a daily dose of 0.6 to 1.8 mg/kg.In some embodiments, the selective inhibitor of SV2A is administeredevery 12 or 24 hours at a daily dose of 0.04-2.5 mg/kg. In someembodiments, the selective inhibitor of SV2A is administered every 12 or24 hours at a daily dose of 0.06-1.8 mg/kg. In some embodiments, theselective inhibitor of SV2A is administered every 12 or 24 hours at adaily dose of 0.001-5 mg/kg. In some embodiments, the selectiveinhibitor of SV2A is administered every 12 or 24 hours at a daily doseof 0.001-0.5 mg/kg. In some embodiments, the selective inhibitor of SV2Ais administered every 12 or 24 hours at a daily dose of 0.01-0.5 mg/kg.

In certain embodiments of the invention, the SV2A inhibitor islevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. The levetiracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredevery 12 or 24 hours at a daily dose of about 1 to 2 mg/kg, or about 0.1to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, orabout 2.0 to 3.0 mg/kg, or about 3.0 to 4.0 mg/kg, or about 2.0 to 4.0mg/kg, or about 0.1 to 5 mg/kg, or about 70 to 140 mg, or about 7 to 180mg, or about 25 to 180 mg, or about 40 to 130 mg, or about 140 to 300mg, or about 200 to 300 mg, or about 140 to 200 mg, or about 7 to 350mg.

In other embodiments, the levetiracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredevery 12 or 24 hours according to one of the daily dose ranges indicatedas “+” listed in Table 1 or Table 2.

TABLE 1 Daily Doses of Levetiracetam (mg/kg) Lower range 0.1 0.4 0.6 1 23 Upper range mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg 1.8 mg/kg + + + + 2mg/kg + + + + 2.5 mg/kg + + + + + 3 mg/kg + + + + + 4 mg/kg + + + + + +5 mg/kg + + + + + +

TABLE 2 Daily Doses of Levetiracetam (mg) in a Human Subject of 70 KGLower range Upper range 7 mg 25 mg 40 mg 70 mg 140 mg 200 mg 130mg + + + + 140 mg + + + + 180 mg + + + + + 200 mg + + + + + 300mg + + + + + + 350 mg + + + + + +

In certain embodiments of the invention, the SV2A inhibitor islevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. The levetiracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredat a daily dose of about 0.1-5 mg/kg, about 1-5 mg/kg, about 1.5-4mg/kg, about 1.8-3.6 mg/kg, about 7-350 mg, about 70-350 mg, about100-300 mg, or about 125-250 mg.

In certain embodiments of the invention, the SV2A inhibitor isbrivaracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. The brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered every 12 or 24 hours at a daily dose of about 0.1 to 0.2mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.04 to 2.5 mg/kg, or about0.06 to 1.8 mg/kg, or about 0.2 to 0.4 mg/kg, or about 7 to 15 mg, orabout 0.7 to 180 mg, or about 2.5 to 180 mg, or about 4.0 to 130 mg, orabout 14 to 30 mg.

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredevery 12 or 24 hours at a daily dose of at least 0.1 mg, 0.5 mg, 0.75mg, 1.0 mg, 1.5 mg, or 2.0 mg, but no more than a daily dose of 2.5 mg,5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg. In other embodiments,the brivaracetam or its pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug is administered every 12 or 24 hours at adaily dose of at least 0.0015 mg/kg, 0.0075 mg/kg, 0.01 mg/kg, 0.015mg/kg, 0.02 mg/kg, or 0.03 mg/kg, but no more than a daily dose of 0.5mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05mg/kg, or 0.04 mg/kg.

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredevery 12 or 24 hours according to one of the daily dose ranges indicatedas “+” listed in Table 3 or Table 4. For example, the brivaracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be administered every 12 or 24 hours at a daily doseof 0.1-35 mg, 0.5-35 mg, 0.75-35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35 mg,0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5mg, 0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0.01-0.5 mg/kg, 0.015-0.5 mg/kg,0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg, 0.0015-0.3 mg/kg,0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0.05mg/kg, or 0.0015-0.04 mg/kg.

TABLE 3 Daily Doses of Brivaracetam (mg/kg) Lower range 0.0015 0.00750.01 0.015 0.02 0.03 Upper range mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg0.04 mg/kg + + + + + + 0.05 mg/kg + + + + + + 0.1 mg/kg + + + + + + 0.15mg/kg + + + + + + 0.2 mg/kg + + + + + + 0.3 mg/kg + + + + + + 0.4mg/kg + + + + + + 0.5 mg/kg + + + + + +

TABLE 4 Daily Doses of Brivaracetam (mg) in a Human Subject of 70 KGLower range Upper range 0.1 mg 0.5 mg 0.75 mg 1.0 mg 1.5 mg 2.0 mg 2.5mg + + + + + + 5 mg + + + + + + 10 mg + + + + + + 15 mg + + + + + + 20mg + + + + + + 25 mg + + + + + + 30 mg + + + + + + 35 mg + + + + + +

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredat a daily dose of at least 0.0015 mg/kg, 0.002 mg/kg, 0.0025 mg/kg,0.005 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg,0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg,0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, but no more than a daily dose of 1mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg,2.2 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.5mg/kg, 4.0 mg/kg, 4.5 mg/kg, or 5.0 mg/kg. In other embodiments, thebrivaracetam or its pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug is administered at a daily dose of at least 0.1mg, 0.15 mg, 0.18 mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg, 2.8 mg,3.0 mg, 3.5 mg, 4.2 mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 10 mg, 15 mg, 20 mg,25 mg, 28 mg, 30 mg, or 35 mg but no more than a daily dose of 70 mg, 80mg, 85 mg, 100 mg, 110 mg, 125 mg, 140 mg, 150 mg, 170 mg, 175 mg, 180mg, 190 mg, 200 mg, 210 mg, 225 mg, 250 mg, 280 mg, 300 mg, or 350 mg.In some embodiments, the brivaracetam or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof may beadministered at a daily dose of 0.0015-5 mg/kg, 0.1-350 mg, 0.01-5mg/kg, 0.7-350 mg, 0.05-4 mg/kg, 3-300 mg, 0.05-2.0 mg/kg, 3-150 mg,0.05-1.5 mg, 3-110 mg, 0.1-1.0 mg/kg, 7-70 mg.

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredaccording to one of the daily dose ranges indicated as “+” listed inTable 5 or Table 6. For example, the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be administered at a daily dose of 0.01-0.8 mg/kg,0.01-1 mg/kg, 0.01-1.5 mg/kg, 0.01-2 mg/kg, 0.01-2.5 mg/kg, 0.01-3mg/kg, 0.01-3.5 mg/kg, 0.01-4 mg/kg, 0.01-5 mg/kg, 0.025-0.8 mg/kg,0.025-1 mg/kg, 0.025-1.5 mg/kg, 0.025-2 mg/kg, 0.025-2.5 mg/kg, 0.025-3mg/kg, 0.025-3.5 mg/kg, 0.025-4 mg/kg, 0.05-0.8 mg/kg, 0.05-1 mg/kg,0.05-1.5 mg/kg, 0.05-2 mg/kg, 0.05-2.5 mg/kg, 0.05-3 mg/kg, 0.05-3.5mg/kg, 0.05-4 mg/kg, 0.075-0.8 mg/kg, 0.075-1 mg/kg, 0.075-1.5 mg/kg,0.075-2 mg/kg, 0.075-2.5 mg/kg, 0.075-3 mg/kg, 0.075-3.5 mg/kg, 0.075-4mg/kg, 0.1-0.8 mg/kg, 0.1-1 mg/kg, 0.1-1.5 mg/kg, 0.1-2 mg/kg, 0.1-2.5mg/kg, 0.1-3 mg/kg, 0.1-3.5 mg/kg, 0.1-4 mg/kg, 0.2-0.8 mg/kg, 0.2-1mg/kg, 0.2-1.5 mg/kg, 0.2-2 mg/kg, 0.2-2.5 mg/kg, 0.2-3 mg/kg, 0.2-3.5mg/kg, 0.2-4 mg/kg, 0.5-0.8 mg/kg, 0.5-1 mg/kg, 0.5-1.5 mg/kg, 0.5-2mg/kg, 0.5-2.5 mg/kg, 0.5-3 mg/kg, 0.5-3.5 mg/kg, or 0.5-4 mg/kg; or0.7-50 mg, 0.7-75 mg, 0.7-100 mg, 0.7-150 mg, 0.7-180 mg, 0.7-225 mg,0.7-250 mg, 0.7-280 mg, 1.8-50 mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg,1.8-180 mg, 1.8-225 mg, 1.8-250 mg, 1.8-280 mg, 3.5-50 mg, 3.5-75 mg,3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-225 mg, 3.5-250 mg, 3.5-280 mg,5-50 mg, 5-75 mg, 5-100 mg, 5-150 mg, 5-180 mg, 5-225 mg, 5-250 mg,5-280 mg, 7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg, 7-180 mg, 7-225 mg,7-250 mg, 7-280 mg, 15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg,15-225 mg, 15-250 mg, 15-280 mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150mg, 35-180 mg, 35-225 mg, 35-250 mg, or 35-280 mg.

TABLE 5 Daily Doses of Brivaracetam (mg/kg) Lower range Upper range0.0015 0.01 0.025 0.04 0.05 0.075 0.1 0.2 0.5 0.8 + + + + + + + + +1 + + + + + + + + + 1.5 + + + + + + + + + 2 + + + + + + + + +2.5 + + + + + + + + + 3 + + + + + + + + + 3.5 + + + + + + + + +4 + + + + + + + + + 5 + + + + + + + + +

TABLE 6 Daily Doses of Brivaracetam (mg) in a Human Subject of 70 KGLower range Upper range 0.1 0.7 1.8 3.0 3.5 5 7 15 3550 + + + + + + + + + 75 + + + + + + + + + 100 + + + + + + + + +110 + + + + + + + + + 150 + + + + + + + + + 180 + + + + + + + + +225 + + + + + + + + + 250 + + + + + + + + + 280 + + + + + + + + +300 + + + + + + + + + 350 + + + + + + + + +

In certain embodiments of the invention, the SV2A inhibitor isseletracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. In some embodiments, the seletracetam orits pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered every 12 or 24 hours at a daily dose ofat least 0.1 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, or 2.0 mg, but no morethan a daily dose of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or35 mg. In other embodiments, the seletracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered every 12 or 24 hours at a daily dose of at least 0.0015mg/kg, 0.0075 mg/kg, 0.01 mg/kg, 0.015 mg/kg, 0.02 mg/kg, or 0.03 mg/kg,but no more than a daily dose of 0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05 mg/kg, or 0.04 mg/kg.

In certain embodiments of the invention, the seletracetam or itspharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug is administered according to one of the daily dose rangesindicated as “+” listed in Table 7 or Table 8. For example, theseletracetam or its pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug may be administered every 12 or 24 hours at adaily dose of 0.1-35 mg, 0.5-35 mg, 0.75-35 mg, 1.0-35 mg, 1.5-35 mg,2.0-35 mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0.1-5mg, 0.1-2.5 mg, 0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0.01-0.5 mg/kg,0.015-0.5 mg/kg, 0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg,0.0015-0.3 mg/kg, 0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg,0.0015-0.05 mg/kg, or 0.0015-0.04 mg/kg.

TABLE 7 Daily Doses of Selectracetam (mg/kg) Lower range 0.0015 0.00750.01 0.015 0.02 0.03 Upper range mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg0.04 mg/kg + + + + + + 0.05 mg/kg + + + + + + 0.1 mg/kg + + + + + + 0.15mg/kg + + + + + + 0.2 mg/kg + + + + + + 0.3 mg/kg + + + + + + 0.4mg/kg + + + + + + 0.5 mg/kg + + + + + +

TABLE 8 Daily Doses of Seletracetam (mg) in a Human Subject of 70 KGLower range Upper range 0.1 mg 0.5 mg 0.75 mg 1.0 mg 1.5 mg 2.0 mg 2.5mg + + + + + + 5 mg + + + + + + 10 mg + + + + + + 15 mg + + + + + + 20mg + + + + + + 25 mg + + + + + + 30 mg + + + + + + 35 mg + + + + + +

In other embodiments, the seletracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredat a daily dose of at least 0.0015 mg/kg, 0.002 mg/kg, 0.0025 mg/kg,0.005 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg,0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg,0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, but no more than a daily dose of 1mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg,2.2 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.5mg/kg, 4.0 mg/kg, 4.5 mg/kg, or 5.0 mg/kg. In other embodiments, theseletracetam or its pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug is administered at a daily dose of at least 0.1mg, 0.15 mg, 0.18 mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg, 2.8 mg,3.0 mg, 3.5 mg, 4.2 mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 10 mg, 15 mg, 20 mg,25 mg, 28 mg, 30 mg, or 35 mg but no more than a daily dose of 70 mg, 80mg, 85 mg, 100 mg, 110 mg, 125 mg, 140 mg, 150 mg, 170 mg, 175 mg, 180mg, 190 mg, 200 mg, 210 mg, 225 mg, 250 mg, 280 mg, 300 mg, or 350 mg.In some embodiments, the brivaracetam or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof may beadministered at a daily dose of 0.0015-5 mg/kg, 0.1-350 mg, 0.01-5mg/kg, 0.7-350 mg, 0.05-4 mg/kg, 3-300 mg, 0.05-2.0 mg/kg, 3-150 mg,0.05-1.5 mg, 3-110 mg, 0.1-1.0 mg/kg, 7-70 mg.

In other embodiments, the seletracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredaccording to one of the daily dose ranges indicated as “+” listed inTable 9 or Table 10. For example, the seletracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be administered at a daily dose of 0.01-0.8 mg/kg,0.01-1 mg/kg, 0.01-1.5 mg/kg, 0.01-2 mg/kg, 0.01-2.5 mg/kg, 0.01-3mg/kg, 0.01-3.5 mg/kg, 0.01-4 mg/kg, 0.01-5 mg/kg, 0.025-0.8 mg/kg,0.025-1 mg/kg, 0.025-1.5 mg/kg, 0.025-2 mg/kg, 0.025-2.5 mg/kg, 0.025-3mg/kg, 0.025-3.5 mg/kg, 0.025-4 mg/kg, 0.05-0.8 mg/kg, 0.05-1 mg/kg,0.05-1.5 mg/kg, 0.05-2 mg/kg, 0.05-2.5 mg/kg, 0.05-3 mg/kg, 0.05-3.5mg/kg, 0.05-4 mg/kg, 0.075-0.8 mg/kg, 0.075-1 mg/kg, 0.075-1.5 mg/kg,0.075-2 mg/kg, 0.075-2.5 mg/kg, 0.075-3 mg/kg, 0.075-3.5 mg/kg, 0.075-4mg/kg, 0.1-0.8 mg/kg, 0.1-1 mg/kg, 0.1-1.5 mg/kg, 0.1-2 mg/kg, 0.1-2.5mg/kg, 0.1-3 mg/kg, 0.1-3.5 mg/kg, 0.1-4 mg/kg, 0.2-0.8 mg/kg, 0.2-1mg/kg, 0.2-1.5 mg/kg, 0.2-2 mg/kg, 0.2-2.5 mg/kg, 0.2-3 mg/kg, 0.2-3.5mg/kg, 0.2-4 mg/kg, 0.5-0.8 mg/kg, 0.5-1 mg/kg, 0.5-1.5 mg/kg, 0.5-2mg/kg, 0.5-2.5 mg/kg, 0.5-3 mg/kg, 0.5-3.5 mg/kg, or 0.5-4 mg/kg; or0.7-50 mg, 0.7-75 mg, 0.7-100 mg, 0.7-150 mg, 0.7-180 mg, 0.7-225 mg,0.7-250 mg, 0.7-280 mg, 1.8-50 mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg,1.8-180 mg, 1.8-225 mg, 1.8-250 mg, 1.8-280 mg, 3.5-50 mg, 3.5-75 mg,3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-225 mg, 3.5-250 mg, 3.5-280 mg,5-50 mg, 5-75 mg, 5-100 mg, 5-150 mg, 5-180 mg, 5-225 mg, 5-250 mg,5-280 mg, 7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg, 7-180 mg, 7-225 mg,7-250 mg, 7-280 mg, 15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg,15-225 mg, 15-250 mg, 15-280 mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150mg, 35-180 mg, 35-225 mg, 35-250 mg, or 35-280 mg.

TABLE 9 Daily Doses of Selectracetam (mg/kg) Lower range Upper range0.0015 0.01 0.025 0.04 0.05 0.075 0.1 0.2 0.5 0.8 + + + + + + + + +1 + + + + + + + + + 1.5 + + + + + + + + + 2 + + + + + + + + +2.5 + + + + + + + + + 3 + + + + + + + + + 3.5 + + + + + + + + +4 + + + + + + + + + 5 + + + + + + + + +

TABLE 10 Daily Doses of Selectracetam (mg) in a Human Subject of 70 KGLower range Upper range 0.1 0.7 1.8 3.0 3.5 5 7 15 3550 + + + + + + + + + 75 + + + + + + + + + 100 + + + + + + + + +110 + + + + + + + + + 150 + + + + + + + + + 180 + + + + + + + + +225 + + + + + + + + + 250 + + + + + + + + + 280 + + + + + + + + +300 + + + + + + + + + 350 + + + + + + + + +

The SV2A inhibitor or its pharmaceutically acceptable salt, hydrate,solvate, polymorph, and prodrug may be administered at a subtherapeuticdosage levels when provided in combination with an antipsychotic or itspharmaceutically acceptable salt, hydrate, solvate, polymorph andprodrug, due to an antipsychotic-dependent increase in the therapeuticindex of the SV2A inhibitor. In some embodiments, the increase in thetherapeutic index of the SV2A inhibitor, due to the combination with anantipsychotic, is greater than the therapeutic index of the SV2Ainhibitor administered in the absence of the antipsychotic by at leastabout 1.5× or 2.0× or 2.5× or 3.0× or 3.5× or 4.0× or 4.5× or 5.0× or5.5× or 6.0× or 6.5× or 7.0× or 7.5× or 8.0× or 8.5× or 9.0× or 9.5× or10×, or greater than about 10×. In some embodiments, combinations of anSV2A inhibitor with an antipsychotic reduces the dosage of the SV2Ainhibitor required for its therapeutic effect. In some embodiments, theamount of the SV2A inhibitor administered in combination with theantipsychotic is a subtherapeutic amount. In some embodiments, the SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate andpolymorph, or prodrug thereof is administered at a daily dose of lessthan 5 mg/kg, less than 2.5 mg/kg, less than 2 mg/kg, less than 1.5mg/kg, less than 1 mg/kg, less than 0.5 mg/kg, less than 0.1 mg/kg, lessthan 0.05 mg/kg, less than 0.01 mg/kg, less than 0.005 mg/kg, or lessthan 0.001 mg/kg. In some embodiments, such subtherapeutic amount, maybe, for example, a daily dose of less than 7 mg/kg, less than 6 mg/kg,less than 5 mg/kg, less than 4 mg/kg, less than 3.8 mg/kg, less than 3.6mg/kg, less than 3.4 mg/kg, less than 3.2 mg/kg, less than 3 mg/kg, lessthan 2.9 mg/kg, less than 2.8 mg/kg, less than 2.7 mg/kg, less than 2.6mg/kg, less than 2.5 mg/kg, less than 2.4 mg/kg, less than 2.3 mg/kg,less than 2.2 mg/kg, less than 2.1 mg/kg, less than 2 mg/kg, less than1.5 mg/kg, less than 1 mg/kg, less than 0.5 mg/kg, less than 0.1 mg/kg,less than 0.05 mg/kg, less than 0.01 mg/kg, or less than 0.0015 mg/kg;or less than 500 mg, less than 420 mg, less than 400 mg, less than 350mg, less than 300 mg, less than 280 mg, less than 270 mg, less than 260mg, less than 250 mg, less than 240 mg, less than 230 mg, less than 225mg, less than 220 mg, less than 210 mg, less than 200 mg, less than 190mg, less than 180 mg, less than 175 mg, less than 170 mg, less than 150mg, less than 140 mg, less than 125 mg, less than 120 mg, less than 110mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg,less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, lessthan 60 mg, less than 55 mg, less than 50 mg, less than 45 mg, less than40 mg, less than 35 mg, less than 30 mg, less than 28 mg, less than 25mg, less than 20 mg, less than 15 mg, less than 12 mg, less than 10 mg,less than 9 mg, less than 8 mg, less than 7 mg, less than 6 mg, lessthan 5.5 mg, less than 5 mg, less than 4.2 mg, less than 3.5 mg, lessthan 3 mg, less than 2.8 mg, less than 2.5 mg, less than 2.0 mg, lessthan 1.5 mg, less than 0.7 mg, less than 0.35 mg, less than 0.18 mg,less than 0.15 mg, or less than 0.1 mg is administered. The SV2Ainhibitors that can be used in the foregoing embodiments include, forexample, levetiracetam, brivaracetam, and seletracetam or theirpharmaceutically acceptable salt, hydrate, solvate or polymorph, orprodrug thereof

In certain embodiments of the invention, the seletracetam or itspharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug is administered according to one of the daily dose rangesindicated above for levetiracetam.

In some embodiments, the antipsychotic useful in the present inventionis a typical antipsychotic. Generally the amount of a typicalantipsychotic administered to a patient is an amount sufficient to havea therapeutic effect. In a preferred embodiment the amount of a typicalantipsychotic administered to a patient is an amount sufficient to treatat least one symptom or sign of schizophrenia or bipolar disorder (inparticular, mania), wherein the one sign or symptom may include, but arenot limited to, any of those described above, including, for example,delusions, hallucinations, disorganized speech (e.g., frequentderailment or incoherence), grossly disorganized or catatonic behaviorand negative symptoms (e.g., affective flattening, alogia, avolition).One skilled in the art will recognize that the amount of typicalantipsychotic will vary with many factors including the potency of thetypical antipsychotic, the age and weight of the patient, and theseverity of the condition or disorder to be treated. The dosages of thedrugs used in the present invention can, in the final analysis, be setby the physician in charge of the case, using knowledge of the drugs,the properties of the drugs in combination as determined in clinicaltrials, and the characteristics of the patient, including diseases otherthan that for which the physician is treating the patient.

In some embodiments, the antipsychotic useful in the present inventionis an atypical antipsychotic. Generally the amount of an atypicalantipsychotic administered to a patient is an amount sufficient to havea therapeutic effect. In a preferred embodiment the amount of anatypical antipsychotic administered to a patient is an amount sufficientto treat at least one symptom or sign of schizophrenia or bipolardisorder (in particular, mania), wherein the one sign or symptom mayinclude, but are not limited to, any of those described above,including, for example, delusions, hallucinations, disorganized speech(e.g., frequent derailment or incoherence), grossly disorganized orcatatonic behavior and negative symptoms (e.g., affective flattening,alogia, avolition). One skilled in the art will recognize that theamount of atypical antipsychotic will vary with many factors includingthe potency of the atypical antipsychotic, the age and weight of thepatient, and the severity of the condition or disorder to be treated.The dosages of the drugs used in the present invention can, in the finalanalysis, be set by the physician in charge of the case, using knowledgeof the drugs, the properties of the drugs in combination as determinedin clinical trials, and the characteristics of the patient, includingdiseases other than that for which the physician is treating thepatient.

Non-limiting daily dosage amounts for several atypical antipsychoticsare provided herein:

Aripiprazole, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, up to about 30 mg/day or about 10-15 mg/day;Asenapine, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day,about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in someembodiments, about 10 mg/day;Clozapine, about 0.1-1000 mg/day, about 1-900 mg/day, about 5-900mg/day, about 10-900 mg/day, about 100-900 mg/day, about 100-800 mg/dayor about 100-750 mg/day, and in some embodiments, about 150-450 mg/dayor about 300-450 mg/day;Iloperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, about 12-24 mg/day;Olanzapine, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, about 10-15 mg/day;Lurasidone, about 0.1-500 mg/day, about 1-500 mg/day, about 1-250mg/day, about 10-250 mg/day, about 10-100 mg/day, or about 20-100mg/day, and in some embodiments, about 40-80 mg/day;Paliperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, about 6 mg/day;Quetiapine, about 0.1-1000 mg/day, about 1-900 mg/day, about 1-800mg/day, about 50-800, about 100-800, or about 200-800 mg/day, and insome embodiments, about 150-750 mg/day, about 300 mg/day or about400-800 mg/day;Risperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, about 4-8 mg/day or 1-6 mg/day;Ziprasidone, about 0.1-250 mg/day, about 1-150 mg/day, about 1-100mg/day, about 20-100, or about 20-80 mg/day, and in some embodiments, upto about 40 mg/day, or up to about 80 mg/day or about 40-80 mg/day.

For repeated administrations over several days or weeks or longer,depending on the condition, the treatment is sustained until asufficient level of cognitive function is achieved.

The antipsychotic or a salt, hydrate, solvate, polymorph, or prodrugthereof may be administered at dosage levels distinct from conventionallevels (e.g., at subtherapeutic doses) when provided in combination withSV2A inhibitor, due to an SV2A inhibitor-dependent increase in theantipsychotic's therapeutic index. In some embodiments, the increase inthe antipsychotic's therapeutic index due to the combination with SV2Ainhibitor is greater than the therapeutic index of the antipsychoticadministered in the absence of an SV2A inhibitor by at least about 1.5×or 2.0× or 2.5× or 3.0× or 3.5× or 4.0× or 4.5× or 5.0× or 5.5× or 6.0×or 6.5× or 7.0× or 7.5× or 8.0× or 8.5× or 9.0× or 9.5× or 10×, orgreater than about 10×. In some embodiments, combination of anantipsychotic with the SV2A inhibitor reduces the dosage of theantipsychotic required for its therapeutic effect. In some embodiments,the antipsychotic is an atypical antipsychotic. When used in combinationwith SV2A inhibitor, such atypical antipsychotic is administered at adose lower than required for its therapeutic effect when administered inthe absence of SV2A inhibitor.

The frequency of administration of the composition of this invention maybe adjusted over the course of the treatment, based on the judgment ofthe administering physician. It will be clear that the SV2A inhibitorand the antipsychotic and their salts, hydrates, solvates, polymorphsand prodrugs can be administered at different dosing frequencies orintervals. For example, SV2A inhibitor can be administered daily(including multiple doses per day) or less frequently. An antipsychoticcan be administered daily (including multiple doses per day) or lessfrequently. In some embodiments, sustained continuous releaseformulations of an SV2A inhibitor and an antipsychotic may be desired.Various formulations and devices for achieving sustained release areknown in the art.

The use of a combination of an SV2A inhibitor and an antipsychotic mayreduce the amount of the antipsychotic necessary for treatment ofschizophrenia or bipolar disorder (in particular, mania), and may thusreduce the side effects caused by the antipsychotics. In particular, thecombination of an SV2A inhibitor with a reduced amount of antipsychoticmay reduce the side effects without negatively impacting efficacy.Accordingly, in some embodiments, a subtherapeutic amount ofantipsychotic is administered.

In some embodiments, a suitable amount of the SV2A inhibitor isadministered so as to reduce the dose of the antipsychotic by at leastabout 20%, at least about 30%, at least about 40%, or at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90% or more from to the dose of the antipsychotic normallyused when administered alone (i.e., individually and not in combinationwith other therapeutic agents or compounds). The reduction may bereflected in terms of amount administered at a given administrationand/or amount administered over a given period of time (reducedfrequency).

In certain embodiments of the invention, the combined administration ofSV2A inhibitor or a salt, hydrate, solvate, polymorph, and prodrugthereof and an antipsychotic or a salt, hydrate, solvate, polymorph, andprodrug thereof can attain a longer or improved therapeutic effect inthe subject than that attained by administering only the SV2A inhibitoror only the antipsychotic, by at least about 1.5×, or 2.0×, or 2.5×, or3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greaterthan about 10×.

Compositions of this Invention

In one aspect, the invention provides compositions comprising an SV2Ainhibitor and at least one antipsychotic and their salts, hydrates,solvates, polymorphs and prodrugs. In some embodiments, the SV2Ainhibitor and the antipsychotic may be present in a single dosage unit(e.g., combined together in one capsule, tablet, powder, or liquid,etc.). In some embodiments of this aspect of the invention, theinvention provides compositions comprising an SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in an extended release form and an antipsychotic and itssalts, hydrates, solvates, polymorphs, or prodrugs in an extendedrelease form. In some embodiments of this aspect of the invention, theinvention provides compositions comprising an SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in a form that is not extended release and anantipsychotic and its salts, hydrates, solvates, polymorphs, or prodrugsin a form that is not extended release. In some embodiments of thisaspect of the invention, the invention provides compositions comprisingan SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof in an extended release form andan antipsychotic and its salts, hydrates, solvates, polymorphs, orprodrugs in a form that is not extended release. In some embodiments ofthis aspect of the invention, the invention provides compositionscomprising an SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in a form that is notextended release and an antipsychotic and its salts, hydrates, solvates,polymorphs, or prodrugs in an extended release form. In someembodiments, the extended release SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof presentin the composition does not affect the pharmacokinetics or the half-lifeclearance of the antipsychotic or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof present in the samecomposition. In some embodiments, the extended release antipsychotics orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof present in the composition does not affect thepharmacokinetics or the half-life clearance of SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof present in the same composition. In some embodiments,the extended release form includes without limitation a controlledrelease form, a prolonged release form, a sustained release form, adelayed release form, or a slow release form. In some embodiments, theform that is not extended release includes, without limitation, animmediate release. In some embodiments, the composition includeslevetiracetam, or seletracetam, or brivaracetam, or a derivative or ananalog or a pharmaceutically acceptable salt, hydrate, solvate, orpolymorph, or prodrug thereof as the SV2A inhibitor, and includes atleast one antipsychotic and their salts, hydrates, solvates, polymorphsand prodrugs. The composition described herein can contain more than oneSV2A inhibitor and/or more than one antipsychotic.

The compositions described herein can further contain pharmaceuticallyacceptable excipient(s) and may contain other agents that serve toenhance and/or complement the effectiveness of the SV2A inhibitor and/orthe antipsychotic. The compositions may also contain additional agentsknown to be useful for treating schizophrenia or bipolar disorder (inparticular, mania).

The SV2A inhibitor and the antipsychotic suitable for the compositionsof this invention may be selected from any of those as described above.In some embodiments, the SV2A inhibitor is selected from any of thosedescribed above; and the antipsychotic is selected from (1) atypical andtypical antipsychotics (such as those described above); (2) agents thatare dopaminergic agents (such as dopamine D1 receptor antagonists oragonists, dopamine D₂ receptor antagonists or partial agonists, dopamineD3 receptor antagonists or partial agonists, dopamine D4 receptorantagonists), glutamatergic agents, NMDA receptor positive allostericmodulators, glycine reuptake inhibitors, glutamate reuptake inhibitor,metabotropic glutamate receptors (mGluRs)agonists or positive allostericmodulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptorglur5 positive allosteric modulators (PAMs), M1 muscarinic acetylcholinereceptor (mAChR) positive allosteric modulators (PAMs), histamine H3receptor antagonists, AMPA/kainate receptor antagonists, ampakines(CX-516), glutathione prodrugs, noradrenergic agents (such as alpha-2adrenergic receptor agonists or antagonists and COMT inhibitors),serotonin receptor modulators (such as 5-HT_(2A) receptor antagonists,5-HT_(1A) receptor partial agonists, 5-HT_(2C) agonists, and 5-HT6antagonists), cholinergic agents (such as alpha-7 nicotinic receptoragonists, alpha4-beta2 nicotinic receptor agonists, allostericmodulators of nicotinic receptors and acetylcholinesterase inhibitors,muscarinic receptor agonists and antagonists), cannabinoid CB1antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO Binhibitors, PDE10 inhibitors, nNOS inhibits, neurosteroids, andneurotrophic factors, including, e.g., those specific such agentsdescribed above, and (3) any compounds that are useful in treating oneor more sign or symptoms of schizophrenia or bipolar disorder (inparticular, mania) (including, e.g., the agents disclosed in any of theabove-listed patents or patent application publications), andpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs thereof. In some embodiments, the SV2A inhibitor is selectedfrom the group consisting of levetiracetam, seletracetam, andbrivaracetam or derivatives or analogs or pharmaceutically acceptablesalts, or solvates, or hydrates, or polymorphs, or prodrugs thereof; andthe antipsychotic is an atyptical antipsychotic selected from, e.g.,aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. Insome embodiments, the SV2A inhibitor is selected from levetiracetam orderivatives or analogs or pharmaceutically acceptable salts, orsolvates, or hydrates, or polymorphs, or prodrugs thereof; and theantipsychotic is an atyptical antipsychotic selected from, e.g.,aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs thereof

The composition described herein can contain more than one SV2Ainhibitor and/or more than one antipsychotic. In some embodiments, theSV2A inhibitor and the antipsychotic are in a single dosage form, in aunit dosage form, in separate dosage forms, or in separate dosage formspackaged together.

The compositions described herein can further contain pharmaceuticallyacceptable excipient(s) and may contain other agents that serve toenhance and/or complement the effectiveness of the SV2A inhibitor and/orthe antipsychotic. The compositions may also contain additional agentsknown to be useful for treating cognitive function disorder.

The composition in the present invention may be in solid dosage formssuch as capsules, tablets, dragrees, pills, lozenges, powders andgranule. Where appropriate, they may be prepared with coatings such asenteric coatings or they may be formulated so as to provide controlledreleases of one or more active ingredient such as sustained or prolongedrelease according to methods well known in the art. In certainembodiments, the composition is in form of a slow, controlled, orextended release. The term “extended release” is widely recognized inthe art of pharmaceutical sciences and is used herein to refer to acontrolled release of an active compound or agent from a dosage form toan environment over (throughout or during) an extended period of time,e.g. greater than or equal to one hour. An extended release dosage formwill release drug at substantially constant rate over an extended periodof time or a substantially constant amount of drug will be releasedincrementally over an extended period of time. The term “extendedrelease” used herein includes the terms “controlled release”, “prolongedrelease”, “sustained release”, or “slow release”, as these terms areused in the pharmaceutical sciences. In some embodiments, the extendedrelease dosage is administered in the form of a patch or a pump. Thecomposition may also be in liquid dosage forms including solutions,emulsions, suspensions, syrups, and elixirs.

The compositions may be specifically formulated for administration byany suitable route as described herein and known in the art.Compositions for parental administration include sterile aqueous andnonaqueous injectable solutions, dispersions, suspensions or emulsionsas well as sterile powders to be reconstituted in sterile injectablesolutions or dispersions prior to use. Compositions for intraoral andoral delivery (including sublingual and buccal administration, e.g.Danckwerts et al, and oral) include but are not limited to bioadhesivepolymers, tablets, patches, liquids and semisolids (see e.g., Smart etal). Compositions for respiratory delivery (pulmonary and nasaldelivery) include but are not limited to a variety of pressurizedmetered dose inhalers, dry powder inhalers, nebulizers, aqueous mistinhalers, drops, solutions, suspensions, sprays, powders, gels,ointments, and specialized systems such as liposomes and microspheres(see e.g. Owens et al, “Alternative Routes of Insulin Delivery” andMartini et al). Compositions for transdermal delivery include but arenot limited to colloids, patches, and microemulsions. Other suitableadministration forms for the above and other include depot injectableformulations, suppositories, sprays, ointments, cremes, gels, inhalants,dermal patches, implants etc.

The compositions may also contain adjuvants, such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption, such as aluminum monostearate andgelatin.

Therapeutic formulations can be prepared by methods well known in theart of pharmacy, see, e.g., Goodman et al., 2001; Ansel, et al., 2004;Stoklosa et al., 2001; and Bustamante, et al., 1993.

In certain embodiments of the invention, a composition containing anSV2A inhibitor and an antipsychotic and their salts, hydrates, solvates,polymorphs and prodrugs comprises an amount of the SV2A inhibitorbetween 0.07 and 350 mg, or between 50 and 200 mg, or between 3 and 50mg. In some embodiments, the amount of the SV2A inhibitor is less than350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than100 mg, less than 50 mg, less than 10 mg, less than 5 mg, less than 1mg, less than 0.5 mg, less than 0.1 mg, or less than 0.07 mg. In certainembodiments of the invention, a composition containing an SV2A inhibitoror its pharmaceutically acceptable salt, hydrate, solvate or polymorphcomprises the SV2A inhibitor in an amount of 0.07-60 mg, 0.07-350 mg,25-60 mg, 25-125 mg, 50-250 mg, 5-140 mg, 0.7-180 mg, 125-240 mg, 3-50mg, or 3-60 mg. In some embodiments, a composition containing an SV2Ainhibitor or its pharmaceutically acceptable salt, hydrate, solvatepolymorph, or prodrugs comprises the SV2A inhibitor in an amount of0.05-35 mg. In some embodiments of the composition of the presentinvention, the SV2A inhibitor may be selected from the group consistingof levetiracetam, brivaracetam, and seletracetam or derivatives oranalogs or pharmaceutically acceptable salts, hydrates, solvates,polymorphs or prodrugs thereof, said SV2A inhibitor being present in anamount selected from any of the above.

In some embodiments, the amount of the SV2A inhibitor present in thecomposition is 0.07-60 mg, 0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg,5-140 mg, 0.7-180 mg, 125-240 mg, 3-50 mg, 3-60 mg, 0.05-35 mg, 0.07-60mg, 0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg, 5-15 mg, 5-30 mg, 5-140mg, 0.7-180 mg, 125-240 mg, 3-50 mg, or 0.07-50 mg, or 3-60 mg. In someembodiments, the amount of the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof presentin the composition is less than 350 mg, less than 250 mg, less than 200mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 35mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg,less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg. In someembodiments, the amount of the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof presentin the composition is about 0.1-500 mg, 0.1-300 mg, 0.7-300 mg, 3-300mg, 3-150 mg, 3-110 mg, 7-70 mg, 7-300 mg, 70-300 mg, 100-300 mg,125-250 mg, 0.5-50 mg, 0.5-75 mg, 0.5-100 mg, 0.5-150 mg, 0.5-200 mg,0.5-225 mg, 0.5-250 mg, 0.5-300 mg, 1.5-50 mg, 1.5-75 mg, 1.5-100 mg,1.5-150 mg, 1.5-200 mg, 1.5-225 mg, 1.5-250 mg, 1.5-300 mg, 3-50 mg,3-75 mg, 3-100 mg, 3-150 mg, 3-200 mg, 3-225 mg, 3-250 mg, 3-300 mg,5-50 mg, 5-75 mg, 5-100 mg, 5-150 mg, 5-200 mg, 5-225 mg, 5-250 mg,5-300 mg, 7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg, 7-200 mg, 7-225 mg,7-250 mg, 7-300 mg, 15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-200 mg,15-225 mg, 15-250 mg, 15-300 mg, 30-50 mg, 30-75 mg, 30-100 mg, 30-150mg, 30-200 mg, 30-225 mg, 30-250 mg, or 30-300 mg.

It will be understood by one of ordinary skill in the art that thecompositions and methods described herein may be adapted and modified asis appropriate for the application being addressed and that thecompositions and methods described herein may be employed in othersuitable applications, and that such other additions and modificationswill not depart from the scope hereof.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the embodiments which followthereafter.

In certain embodiments of the invention, a composition comprisinglevetiracetam and an antipsychotic and their salts, hydrates, solvates,polymorphs, prodrugs comprises an amount of the levetiracetam or itssalts, hydrates, solvates, polymorphs, prodrugs between the ranges shownin Table 11 or less than any of the upper ranges shown in Table 11. Incertain embodiments of the invention, a composition comprisingbrivaracetam and an antipsychotic and their salts, hydrates, solvates,polymorphs, prodrugs comprises an amount of the brivaracetam or itssalts, hydrates, solvates, polymorphs, prodrugs between the ranges shownin Table 12 or less than any of the upper ranges shown in Table 12. Incertain embodiments of the invention, a composition comprisingseletracetam and an antipsychotic and their salts, hydrates, solvates,polymorphs, prodrugs comprises an amount of the seletracetam or itssalts, hydrates, solvates, polymorphs, prodrugs between the ranges shownin Table 12 or less than any of the upper ranges shown in Table 12.

TABLE 11 Amount of Levetiracetam Present in the Composition (mg) Lowerrange 7 25 40 70 125 140 200 Upper range mg mg mg mg mg mg mg 130mg + + + + 140 mg + + + + + 180 mg + + + + + + 200 mg + + + + + + 250mg + + + + + + + 300 mg + + + + + + + 350 mg + + + + + + +

TABLE 12 Amount of Selectracetam or Brivaracetam Present in theComposition (mg) Lower range Upper range 0.1 0.7 1.8 3.0 3.5 5 7 15 3550 + + + + + + + + + 75 + + + + + + + + + 100 + + + + + + + + +110 + + + + + + + + + 150 + + + + + + + + + 180 + + + + + + + + +225 + + + + + + + + + 250 + + + + + + + + + 280 + + + + + + + + +300 + + + + + + + + + 350 + + + + + + + + +

EXAMPLES Introduction and Models of Cognitive Impairment

A variety of conditions characterized by cognitive impairment, e.g.,Age-Associated Memory Impairment (AAMI), Mild Cognitive Impairment (MCI)and Age-related Cognitive Decline (ARCD) are believed to be related toaging. Others are related to disease, for example, AD. Animal modelsserve as an important resource for developing and evaluating treatmentsfor such age-related cognitive impairments. Features that characterizeage-related cognitive impairment in animal models typically extend toage-related cognitive impairment in humans. Efficacy in such animalmodels is, thus, predictive of efficacy in humans.

Of available models, a Long-Evans rat model of cognitive impairment isparticularly well suited for distinguishing the difference betweencognitive impairment related to illness and that related to aging.Indeed, extensive behavioral characterization has identified a naturallyoccurring form of cognitive impairment in an outbred strain of agedLong-Evans rats (Charles River Laboratories; Gallagher et al., Behav.Neurosci. 107:618-626, (1993)). In a behavioral assessment with theMorris Water Maze (MWM), rats learn and remember the location of anescape platform guided by a configuration of spatial cues surroundingthe maze. The cognitive basis of performance is tested in probe trialsusing measures of the animal's spatial bias in searching for thelocation of the escape platform. Aged rats in the study population haveno difficulty swimming to a visible platform, but an age-dependentimpairment is detected when the platform is camouflaged, requiring theuse of spatial information. Performance for individual aged rats in theoutbred Long-Evans strain varies greatly. For example, a proportion ofthose rats perform on a par with young adults. However, approximately40-50% fall outside the range of young performance. This variabilityamong aged rats reflects reliable individual differences. Thus, withinthe aged population some animals are cognitively impaired and designatedaged-impaired (AI) and other animals are not impaired and are designatedaged-unimpaired (AU). See, e.g., Colombo et al., Proc. Natl. Acad. Sci.94: 14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10:691-708, (1989); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996); andNicolle et al., J. Neurosci. 19: 9604-9610, (1999).

We used the above-described rat model to identify individual AI and AUrats. We then conducted behavioral assessment on AI rats whileadministering various pharmacological treatments.

Example 1 Increased Gene Expression of SV2A in Aged-Impaired RatsBehavioral Characterization of Young, Aged-Impaired and Aged-UnimpairedRats in Morris Water Maze (MWM)

Behavioral tests are performed on young (4 months old) and aged (24months old) pathogen-free male Long-Evans rats.

The MWM apparatus consists of a large, circular pool (diameter 1.83 m;height, 0.58 m) filled with water (27° C.) that is made opaque throughthe addition of non-toxic pigment or some other substance. In thetypical “hidden platform” version of the test, rats are trained to finda camouflaged white escape platform (height, 34.5 cm) that is positionedin the center of one quadrant of the maze about 1.0 cm below the watersurface. This platform can be retracted to the bottom of the tank orraised to its normal position from outside the maze during behavioraltesting. The location of the platform remains constant from trial totrial. Because there are no local cues that mark the position of theplatform, the rat's ability to locate it efficiently from any startingposition at the perimeter of the pool depends on using informationsurrounding the maze. The maze is surrounded by black curtains to whichwhite patterns are affixed to provide a configuration of spatial cues. Asecond platform (height 37.5 cm), with its surface painted black iselevated 2 cm above the water surface during cue training to control forfactors unrelated to cognition. The behavior of a rat in the pool isrecorded by a camera that is suspended 2.5 m above the center of thepool. The camera is connected to a video tracking system (HVS ImageAdvanced Tracker VP200) and a PC computer running HVS software developedby Richard Baker of HVS Image, Hampton, UK.

The MWM protocol is optimized for sensitivity to the effects of aging oncognition and for measures of reliable individual differences within theaged population of out-bred Long-Evans rats (Gallagher et al. Behav.Neurosci. 107:618-626, (1993)). Rats receive three trials per day for 8consecutive days, using a 60 sec inter-trial interval. On each trainingtrial, the rat is released into the maze from one of four equally spacedstarting positions around the perimeter of the pool. The startingposition varies from trial to trial, thus preventing the use of aresponse strategy (e.g., always turning left from the start location tolocate the escape platform). If a rat does not locate the escapeplatform within 90 sec on any trial, the experimenter guides the rat tothe platform, where it remains for 30 sec. Every sixth trial consists ofa probe trial to assess the development of spatial bias in the maze.During these trials, the rat swims with the platform being refracted tothe bottom of the pool for 30 sec, at which time the platform is raisedto its normal position for completion of the escape trial. At thecompletion of the protocol using the hidden platform, rats are assessedfor cue learning using the visible platform. The location of thisplatform varies from trial to trial in a single session of 6 trainingtrials.

The proximity of the animal's position with respect to the goal is usedto analyze the training trial and probe trial performance. The proximitymeasure is obtained by sampling the position of the animal in the maze(10 times/sec) to provide a record of distance from the escape platformin 1 sec averages. For both probe trials and training trials, acorrection procedure is implemented so that trial performance isrelatively unbiased by differences in distance to the goal from thevarious start locations at the perimeter of the pool. In making thiscorrection, the average swimming speed is calculated for each trial(path length/latency). Then, the amount of time required to swim to thegoal at that speed from the start location used for the trial is removedfrom the record prior to computing trial performance, i.e., cumulativedistance on training trials and average distance from the goal on probetrials. Thus, the scores that are obtained using the proximity measureare designed to reflect search error, representing deviations from anoptimal search, i.e. direct path to the goal and search in the immediatevicinity of that location during probe trials.

Computer records of video-tracking are compiled to provide data on eachrat's performance in the maze. Measures on training trials and probetrials are analyzed by Analysis of Variance (ANOVA).

In one set of trials, the performance during training with the hidden,camouflaged platform differs between the groups of young and aged rats[F (1, 23)=12.69, p<0.002]. In this set of trials, no difference betweenthe groups is observed for the cue training trials with a visibleplatform. In this set of trials, latencies to escape during cue trainingaveraged 9.36 seconds for young and 10.60 seconds for the aged rats.

An average proximity measure on interpolated probe trials is used tocalculate a spatial learning index for each individual subject asdescribed in detail in Gallagher et al., Behav. Neurosci. 107:618-26,(1993). When a rat rapidly learns to search for the platform close toits position, its spatial learning index is low. Overall, in one set oftrials aged rats differed from young rats [F (1, 23)=15.18, p<0.001].Aged rats are classified as either unimpaired or impaired relative tothe learning index profile of the young study population. Aged rats thatfall within the normative range of young rats (index scores <241) aredesignated aged-unimpaired (AU). The remaining aged subjects that haveindex scores outside the range of young performance are designatedaged-impaired (AI).

Preparation of RNA from Behaviorally Characterized Rats

Twenty-four outbred Long-Evans rats, that are behaviorally characterizedas is described above, are killed by live decapitation to obtain freshbrain tissue. The brain is removed, and the dentate gyms hippocampalregion is microdissected from 500 micron sections taken through thetransverse axis of the entire hippocampal formation (both left and righthippocampi) of 24 characterized rats. There are 8 animals in each group(AI, AU, and Y).

Total RNA is isolated using Trizol reagent (Invitrogen, Carlsbad,Calif.) according to the standard protocol (homogenization in Trizolreagent followed by chloroform extraction and isopropanolprecipitation). Total RNA is further purified using the RNeasy mini kit(Qiagen, Valencia, Calif.). cRNA probes are then generated from the RNAsamples at the Johns Hopkins Microarray Core Facility, generallyaccording to Affymetrix specifications.

Briefly, 5 μg of total RNA is used to synthesize first strand cDNA usingoligonucleotide probes with 24 oligo-dT plus T7 promoter as primer(Proligo LLC, Boulder, Calif.), and the SuperScript Choice System(Invitrogen). Following the double stranded cDNA synthesis, the productis purified by phenol-chloroform extraction, and biotinilated anti-sensecRNA is generated through in vitro transcription using the BioArray RNAHigh Yield Transcript Labeling kit (ENZO Life Sciences Inc.,Farmingdale, N.Y.). 15 μg of the biotinilated cRNA is fragmented at 94°C. for 35 min (100 mM Trix-acetate, pH 8.2, 500 mM KOAC, 150 mM MgOAC).10 μg of total fragmented cRNA is hybridized to the RAT genome 230-2Affymetrix GeneChip array for 16 hours at 45° C. with constant rotation(60 rpm).

Affymetrix Fluidics Station 450 is then used to wash and stain thechips, removing the non-hybridized target and incubating with astreptavidin-phycoerythrin conjugate to stain the biotinilated cRNA. Thestaining is then amplified using goat immunoglobulin-G (IgG) as blockingreagent and biotinilated anti-streptavidin antibody (goat), followed bya second staining step with a streptavidin-phycoerythrin conjugate.

For quality control of the total RNA from the samples, the AgilentBioanalyzer, Lab on a Chip technology, is used to confirm that all thesamples had optimal rRNA ratios (1:2, for 18S and 28S, respectively) andclean run patterns.

For quality control of the hybridization, chip image, and comparisonbetween chips, the following parameters are considered: Scaling factor:related to the overall intensity of the chip, to confirm the similarsignal intensity and staining through out the samples; Background:estimation of unspecific or cross-hybridization; Percentage of presentcalls: percentage of transcripts that are considered significantlyhybridized to the chip (present) by the algorithm;Glyseraldehyde-3-phosphate dehydrogenase (GAPDH) (3′/5′): representationof the RNA integrity by measuring the ratio of 3′ to 5′ regions for thehousekeeping gene GAPDH, its presence in the chip and a ratio close to 1advocates for a good integrity of the target (sample); Spikes(BioB/BioC) to confirm the detection level and sensitivity afterhybridization.

Data Analysis of Microarray

Fluorescence is detected using the Affymetrix G3000 GeneArray Scannerand image analysis of each GeneChip is done through the GeneChipOperating System 1.1.1 (GCOS) software from Affymetrix, using thestandard default settings. All of the GeneChip arrays use shortoligonucleotides for genes in an RNA sample.

For comparison between different chips, global scaling is used, scalingall probe sets to target intensity (TGT) of 150. Total number of presentcalls and scaling factors are similar across all chips. Further analysisfor presence/absence and statistical difference is performed on a regionby region basis in the following manner. Probe sets are determined to bepresent in a region if it had a present call in four of eight animals ina single group.

Probe sets are annotated using the Affymetrix annotation of Jun. 20,2005, and all probe sets representing a specific gene are identified.

An ANOVA is conducted on the probe set signal values for all presentprobe sets by combining two groups of animals and comparing them to thethird group. An “AI ANOVA” is performed, where AU group are combinedwith Young group and compared to AI group.

Pearsons's correlations comparing probe set signal values to learningindices are calculated for the aged animals (excluding young) across allpresent probe sets. As shown in FIG. 1, expression of genes encodingSV2A is significantly increased in aged-impaired (AI) individualsrelative to young individuals (Y) and aged-unimpaired individuals (AU)in a set of experiments performed as above. These results show thatincreased SV2A expression is correlated to the development ofage-related cognitive impairment.

Example 2 Effect of Levetiracetam in Aged-Impaired Rats Morris WaterMaze Results

Six Age-Impaired (AI) Long-Evans rats (as characterized above) aretested for their memory of new spatial information in the MWM, underdifferent drug/control treatment conditions (vehicle control and twodifferent dosage levels of levetiracetam). The MWM protocol issubstantially the same as the one described in Example 1. Specificallyfor this study, a retention trial is performed after the trainingtrials, as described below.

AI rats are given six training trials per training day with a 60-secinter-trial interval between each training trial for two consecutivedays. On each training trial, the rat is released in the maze from oneof four equally spaced starting positions around the perimeter of thepool. If the rat does not locate the escape platform within 90 sec onany trial, the experimenter guides the rat to the platform, where itremains for 30 sec. 30 minutes to 1 hour prior to all the trainingtrials on each training day, AI rats are pretreated with one of threedrug conditions: 1) vehicle control (0.9% saline solution); 2)levetiracetam (5 m/kg/day); and 3) levetiracetam (10 mg/kg/day); throughintraperitoneal (i.p.) injection. The same six AI rats are used for theentire trials so that each treatment condition is tested on all sixrats. Therefore, to counterbalance any potential bias, both the locationof the escape platform and the spatial cues surrounding the water mazeare different in the three treatment conditions. Therefore, using oneset of locations and spatial cues, two rats are treated with salinecontrol solution, two with levetiracetam (5 m/kg/day) and two withlevetiracetam (10 mg/kg/day). Using the second set of locations andspatial cues, the two rats that are treated with saline control solutionin the first test are treated with either levetiracetam (5 m/kg/day) orlevetiracetam (10 mg/kg/day), and the two rats that are previouslytreated with levetiracetam (5 m/kg/day) are treated with either salinecontrol solution or levetiracetam (10 mg/kg/day), and the two rats thatare previously treated with levetiracetam (10 mg/kg/day) are treatedwith either saline control solution or levetiracetam (5 m/kg/day). Usingthe last set of locations and spatial cues, the rat groupings are againswitched so that each group is treated with a different condition thanthey have been treated previously.

After the second training day and completion of the twelve trainingtrials (over the two days), the rat is returned to its home cage andplaced in the animal housing room. After a delay of 24 hours from thelast training trial, the rat is given one testing trial (the “retentiontrial”), which is the same MWM task as the training trials, but with theescape platform removed.

For the retention trial, the MWM circular pool is divided into 4quadrants. The particular quadrant where the escape platform is placedin the training trials is referred as “target quadrant”. The particularregion where the platform is located in the training trials is referredas “target annulus”. In the retention trial, the time the AI rats spentswimming in the target quadrant is measured and further plotted as apercentage of total swimming time. FIG. 2 displays the results of onesuch set of retention trials. The time the AI rats spend in the targetannulus is also measured. FIG. 2 displays the results of one such set ofretention trials. Time data are collected for all three drug treatmentconditions.

In the retention trial, whose results are depicted in FIG. 2, the timethe AI rats spend in the target quadrant is approximately 25%, which isa performance equivalent to them having no memory of the platformlocation. This performance does not significantly improve in the grouptreated with levetiractam at 5 mg/kg/day. However, the group treatedwith levetiractam at 10 mg/kg/day demonstrates significantly improvedmemory as compared to vehicle-treated controls, as indicated by asignificant increase in the time spent in the target quadrant toapproximately 35% of total swimming time (see FIG. 2). That level ofperformance is equivalent to young and age-unimpaired rats, indicatingthat treatment with 10 mg/kg/day levetiractam results in a significantrecovery of the AI rats' ability to navigate this MWM. The effectivenessof the 10 mg/kg/day levetiracetam treatment is also seen in the timespent in the target annulus (see FIG. 2).

Radial Arm Maze Results

The effects of levetiracetam on the spatial memory retention ofaged-impaired (AI) rats are assessed in a Radial Arm Maze (RAM)behavioral task using vehicle control and five different dosage levelsof levetiracetam (1.25 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day, 10mg/kg/day and 20 mg/kg/day). RAM behavioral tasks are preformed on tenAI rats. All six treatment conditions are tested on all ten rats, asdescribed above for the MWM test.

The RAM apparatus used consists of eight equidistantly-spaced arms. Anelevated maze arm (7 cm width×75 cm length) projects from each facet ofan octagonal center platform (30 cm diameter, 51.5 cm height). Clearside walls on the arms are 10 cm high and are angled at 65° to form atrough. A food well (4 cm diameter, 2 cm deep) is located at the distalend of each arm. Froot Loops™ (Kellogg Company) are used as rewards.Blocks constructed of Plexiglas™ (30 cm height×12 cm width) can bepositioned to prevent entry to any arm. Numerous extra maze cuessurrounding the apparatus are also provided.

The AI rats are initially subjected to a pre-training test (Chappell etal. Neuropharmacology 37: 481-487, 1998). The pre-training test consistsof a habituation phase (4 days), a training phase on the standardwin-shift task (18 days) and another training phase (14 days) in which abrief delay is imposed between presentation of a subset of armsdesignated by the experimenter (e.g., 5 arms available and 3 armsblocked) and completion of the eight-arm win-shift task (i.e., with alleight arms available).

In the habituation phase, rats are familiarized to the maze for an8-minute session on four consecutive days. In each of these sessionsfood rewards are scattered on the RAM, initially on the center platformand arms and then progressively confined to the arms. After thishabituation phase, a standard training protocol is used, in which a foodpellet is located at the end of each arm. Rats receive one trial eachday for 18 days. Each daily trial terminates when all eight food pelletshave been obtained or when either 16 choices are made or 15 minutes hadelapsed. After completion of this training phase, a second trainingphase is carried out in which the memory demand is increased by imposinga brief delay during the trial. At the beginning of each trial, threearms of the eight-arm maze are blocked. Rats are allowed to obtain foodon the five arms to which access is permitted during this initial‘information phase’ of the trial. Rats are then removed from the mazefor 60 seconds, during which time the barriers on the maze are removed,thus allowing access to all eight arms. Rats are then placed back ontothe center platform and allowed to obtain the remaining food rewardsduring this ‘retention test’ phase of the trial. The identity andconfiguration of the blocked arms varies across trials.

The number of “errors” the AI rats make during the retention test phaseis tracked. An error occurs in the trial if the rats enter an arm fromwhich food had already been retrieved in the pre-delay component of thetrial, or if it re-visits an arm in the post-delay session that hasalready been visited.

After completion of the pre-training test, rats are subjected to trialswith more extended delay intervals, i.e., a one-hour delay, between theinformation phase (presentation with some blocked arms) and theretention test (presentation of all arms). During the delay interval,rats remain off to the side of the maze in the testing room, on carts intheir individual home cages. AI rats are pretreated 30-40 minutes beforedaily trials with a one-time shot of the following six conditions: 1)vehicle control (0.9% saline solution); 2) levetiracetam (1.25mg/kg/day); 3) levetiracetam (2.5 mg/kg/day); 4) levetiracetam (5mg/kg/day); 5) levetiracetam (10 mg/kg/day); 6) levetiracetam (20mg/kg/day); through intraperitoneal (i.p.) injection. Injections aregiven every other day with intervening washout days. Each AI rat istreated with all six conditions within 23 days of testing. Tocounterbalance any potential bias, drug effect is assessed usingascending-descending dose series, i.e., the dose series are given firstin an ascending order and then repeated in a descending order.Therefore, each dose has two determinations.

Parametric statistics (paired t-tests) is used to compare the retentiontest performance of the AI rats in the one-hour delay version of the RAMtask in the context of different doses of levetiracetam and vehiclecontrol (see FIG. 3). The average numbers of errors that occur in thetrials are also significantly fewer with levetiracetam treatment of 5mg/kg/day (average no. of errors±standard error of the mean(SEM)=0.75±0.32) and 10 mg/kg/day (average no. of errors±SEM=0.80±0.27)than using vehicle control (average no. of errors±SEM=2.00±0.42).Relative to vehicle control treatment, levetiracetam significantlyimproves memory performance at 5 mg/kg/day (t(9)=2.18, p=0.057) and 10mg/kg/day (t(9)=2.37, p=0.042).

The radial arm maze task is also used to evaluate the effect of acombination therapy with Levetiracetam (i.p. administration) andvalproate (subcutaneous administration). Levetiracetam, on its own, iseffective in reducing the number of errors by AI rats in the radial armmaze at 5-10 mg/kg doses, but not at 1.25 mg/kg or 2.5 mg/kg. Valproate,on its own, is effective at 100 mg/kg but not at 25 mg/kg or 50 mg/kg.See FIG. 4. Combining the two drugs, however, has a synergistic effect.A combined administration of 50 mg/kg valproate with 2.5 mg/kglevetiracetam, neither being an effective dose when administeredindividually, results in a reduced number of errors in the radial armmaze task.

This result is also obtained at an even lower dose of 1.25 mg/kglevetiracetam combined with 50 mg/kg valproate. See FIG. 5. Anisobologram of levetiracetam and valproate dosages confirms that theeffect of the combined 50 mg/kg valproate and 1.25 mg/kg levetiracetam(VPA 50+LEV 1.25; empty circle) has a synergistic (super-additive)effect. The combined 50 mg/kg valproate and 2.5 mg/kg levetiracetam (VPA50+LEV 2.5; dark circle), on the other hand, has a simple additiveeffect, as indicated by its placement on the line. See FIG. 6.

To calculate the human equivalent dose (HED) for levetiracetam dosagefor treatment of age-dependent cognitive impairment in humans, we employthe formula HED (mg/kg)=rat dose (mg/kg)×0.16 (see Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers, December 2002, Center for Biologics Evaluation andResearch). Therefore, based on the HED calculation, the dosage of 5mg/kg/day in rats is equivalent to 0.8 mg/kg/day in humans and thedosage of 10 mg/kg/day in rats is equivalent to 1.6 mg/kg/day in humans.

The HED calculation is based on body surface area. As a result, it is anestimate of what human dose corresponds to an animal (e.g., rat) dose inthe context of a maximum safe starting dose for clinical trials inhumans. Calculating the HED is typically an initial step in carrying outthe clinical trial of a drug in humans. It is not an indication of theultimate human therapeutic dose. See, “Estimating the Safe Starting Dosein Clinical Trials for Therapeutics in Adult Health Volunteers, December2002, Center for Biologics Evaluation and Research.” Blood/plasma levelsare a far better predictor of therapeutic dose correspondence betweenanimals (e.g., rats) and humans. As described below in Example 7, theactual levetiracetam blood levels of its daily doses in the aMCI patienthuman clinical studies (62.5 mg BID, 125 mg BID, and 250 mg BIDlevetiracetam doses) (see FIGS. 27A, 27B and 27C) and the actuallevetiracetam blood levels of its daily doses of 10 mg/kg and 60 mg/kgin the AI rat experiments are evaluated. Based on the blood levels, thetherapeutically effective human doses that correspond to the effectiverat doses (i.e., 5-10 mg/kg/day) are estimated to be 1.6-3.3 mg/kg/day.Such a dosage would result in the administration of 56-115 mg twice aday in human subjects.

Example 3 Effect of Levetiracetam in human subjects with aMCI

A within-subjects trial of 8 weeks duration, involving 17 amnestic MCI(aMCI) subjects and 17 age-matched controls with a low dose treatment oflevetiracetam is conducted. During the course of the study, each aMCIsubject receives both drug and placebo treatments separately in twoperiods of two weeks each, with the order of treatments among differentaMCI subjects being counterbalanced (see FIG. 7). Age-matched controlsubjects that are treated with placebo serve as a further control.Cognitive testing and fMRI imaging data are obtained from the subjectsafter each two week period of drug/placebo treatment.

Participants and Clinical Characterization

17 right-handed aMCI patients are recruited from the Alzheimer's DiseaseResearch Center (ADRC) at the Johns Hopkins Hospital and otherreferrals. An additional 17 right-handed healthy volunteers arerecruited from the pool of control participants in the ADRC and otherreferrals. All participants are administered the Telephone Interview ofCognitive Status to determine if they are likely to pass the entrycriteria of the study (including criteria for MRI scanning) Allparticipants further undergo neurological, psychiatric, andneuropsychological examination using standardized instruments andmethods. The psychiatric evaluation includes administration of theStructured Clinical Interview for DSM-IV Axis I Disorders and theClinical Dementia Rating (CDR) scale. All aMCI patients have CDR scoresof 0.5. Diagnosis of aMCI is based on the criteria proposed by Petersenet al. (e.g., “Mild cognitive impairment: Aging to Alzheimer's Disease,”Oxford University Press, N.Y. (2003), which include a memory complaint(corroborated by an informant), impaired memory function on testing (1.5standard deviations below norm), otherwise preserved cognitivefunctioning (within 1 standard deviation of norm), no decline infunctional ability, and no dementia. Final aMCI diagnoses are reached byclinical consensus. Exclusion criteria include major neurological orpsychiatric disorders, head trauma with loss of consciousness, historyof drug abuse or dependency, and general contraindications to an MRIexamination (e.g. cardiac pacemaker, aneurysm coils, claustrophobia).Each aMCI subject is required to have a study partner (i.e., aninformant) who can provide information about the subject's dailyfunction and assure that medications are taken appropriately. See FIGS.18A and 18B.

Study Visits:

The study consists of 4 visits over the course of 8 weeks (see FIG. 7).The Baseline Visit is for the purpose of performing medical,neurological, psychiatric, and neurocognitive assessments. Visits 1 and2 are identical to the Baseline Visit but include a fMRI session. TheWashout Visit, at the end of a 4 week washout period, is for the purposeof a brief clinical assessment and initiation of the second drug/placebophase.

Baseline Visit:

At the screening visit, informed consent is obtained from the subject(and an informant in the case of MCI subjects). The subject and theinformant participate in a standardized clinical interview that is usedto determine the degree of the subject's functional impairment in dailylife, based on the Clinical Dementia Rating (CDR) scale. The subject'smedical, neurological, and psychiatric history is obtained (including areview of current medications), as well as the family history ofdementia. Brief medical, neurological and psychiatric exams areconducted (including vital signs). Blood is drawn in order to performstandard laboratory tests that are needed to determine if the subjectmeets the entry criteria. The subject is re-screened forcontraindications to MRI scanning, using the standard form employed atthe Kirby Imaging Center. Brief cognitive testing is performed(described in section on neuropsychological assessment below). Theseassessments are used to determine if the subject meets the entrycriteria. All of the foregoing are completed using standardized forms.If the subject meets entry criteria for the study, the subject is giventhe study medication (drug or placebo, randomly selected), andinstructions about how it should be taken. The subject is advised aboutthe potential for having suicidal thoughts and advised to stop takingthe medication and immediately contact the study physician if thisoccurs.

Visit 1:

At the end of the first drug/placebo period 2 weeks after the BaselineVisit, the medical, neurological and psychiatric evaluations andcognitive testing are repeated. The subject is also clinically evaluatedfor suicidal ideation. Blood is drawn again to repeat the standard testsand to determine whether there are any changes related to drugtreatment; the subject's blood levetiracetam level is also obtained. Allmedication that is dispensed at the Baseline Visit (drug or placebo) iscollected and subject compliance with the medication regimen isassessed. The first fMRI session (with cognitive tests) is conducted onthe same day, either immediately before or immediately after theclinical assessment. Subjects discontinue first period treatment at thisvisit.

Washout Visit:

At the end of a washout period (4 weeks) following Visit 1, the subjectreceives a brief medical screening, including a medical and psychiatricevaluation. Blood is drawn to obtain the blood levetiracetam level (toconfirm washout). The subject is provided with new medication (drug orplacebo, alternated from what is assigned in the previous treatmentperiod) for the final phase of the study with instructions about how itshould be taken.

Visit 2:

At approximately 2 weeks after the Washout Visit (i.e., 2 weeks afterstarting the second treatment period), the medical, neurological andpsychiatric evaluations and the cognitive testing are repeated. Thesubject is clinically evaluated for suicidal ideation. Blood is drawnagain to repeat the standard tests and to determine whether there areany changes related to drug treatment; the subject's blood levetiracetamlevel is also obtained. All medication that is dispensed at the WashoutVisit is collected and subject compliance with the medication regimen isassessed. The second fMRI session (with cognitive tests) is repeated onthe same day, either immediately before or immediately after theclinical assessment.

Neuropsychological Assessment

All participants undergo neuropsychological evaluation at the time ofassessment for treatment efficacy (Visits 1 and 2), as well as at theBaseline Visit. The evaluation occurs outside of the scanner andincludes the Buschke Selective Reminding Test (Buschke and Fuld, 1974)and the Verbal Paired Associates subtest, the Logical Memory subtest,the Visual Reproduction subtest of the Wechsler Memory Scale-Revised(WMS-R) (Wechsler, 1997), and the Benton Visual Retention Test, as thesetasks are particularly sensitive to medial temporal lobe function andearly memory problems (Marquis et al., 2002 and Masur et al., 1994).Additionally, subjects are asked to complete tests of more generalcognitive function such as tests to assess general mental status,executive function, attention and general naming ability. Allneuropsychological tests are administered by a trained researchassistant during a 60-minute session. As the three neuropsychologicalassessments in this study occur within a time period of 8 weeks,different versions of the neuropsychological tests are used to minimizetest specific practice effects. Breaks are provided to the subject asneeded.

Drug Administration

As described above, the drug treatment period is the two weeks precedingVisit 1 or 2 (with the two week period preceding the other Visit beingthe placebo phase). For the subjects receiving the drug treatment, halfa scored 250 mg tablet of levetiracetam is used to achieve a dose of 125mg/kg twice a day, which is approximately 3.6 mg/kg/day (assuming anaverage adult human weight of 70 kg).

All drug and placebo preparations are performed on a 1:1 allocation. Thepharmacy randomizes patients as they enroll, and keeps a list of drugassignment.

Levetiracetam is rapidly and almost completely absorbed after oraladministration, and its bioavailability is not affected by food. Plasmahalf-life of levetiracetam is approximately 7±1 hour (expected to be9-10 hours in elderly due to decreased renal function). Absorption israpid, with peak plasma concentrations occurring about 1 hour followingoral administration. Steady state can be achieved after 2 days ofmultiple twice-daily dosing.

A typical starting dose of levetiracetam in treating epilepsy in humansis 500 mg twice a day, which is approximately 14.3 mg/kg/day. The dosageis then is increased until optimal efficacy, typically up to 50mg/kg/day. Thus, the dose that is used in this experiment is a quarterof the lowest human dose used for treating epilepsy.

Even lower dosages, e.g., of 25-60 mg twice a day, are contemplated,based on the results of previous animal studies that indicate low-doseefficacy. The highest effective doses of levetiracetam used in theanimal model are 5-10 mg/kg (given acutely). The human equivalent dose(HED), calculated as described above, of this dosage for treatment ofage-dependent cognitive impairment in humans is equivalent to 0.8-1.6mg/kg/day (or 28-56 mg twice a day).

MRI Data Acquisition

Imaging data are obtained through high-resolution methods developed inthe Stark laboratory. Data are collected on a Phillips 3 Tesla scanner(Eindhoven, The Netherlands) equipped with an 8-channel SENSE(Sensitivity Encoding) head coil, located at the F.M. Kirby ResearchCenter for Functional Brain Imaging at the Kennedy Krieger Institute(Baltimore, Md.). High-resolution echo-planar images are collected usingan acquisition matrix of 64×64, a repetition time of 1500 milliseconds,an echo time of 30 milliseconds, a flip angle of 70 degrees, a SENSEfactor of 2, and an isotropic resolution of 1.5 mm×1.5 mm×1.5 mm with nogap. Nineteen oblique slices are acquired parallel to the principallongitudinal axis of the hippocampus and covered the entire medialtemporal lobe region bilaterally. In addition to the functional runs, awhole-brain MPRAGE structural scan (parameters: 150 oblique slices, 1 mmisotropic resolution) is acquired.

Image Analysis

Data analysis is carried out using the Analysis for FunctionalNeuroimages (AFNI, release 2008_(—)07_(—)18_(—)1710) software. Imagesare first co-registered to correct for within- and across-scan headmotion. Acquisitions in which a significant motion event occur (morethan 3 degrees of rotation or 2 mm of translation in any directionrelative to prior acquisition), plus and minus one time repetition for1.5 seconds, are excluded from the analyses. Structural anatomical dataare registered to standard stereotaxic space (Talairach & Tournoux,1988), and the same parameters are subsequently applied to thefunctional data. Behavioral vectors are produced to model differenttrial types.

The ROI-LDDMM (large deformation diffeomorphic metric mapping of theregion of interest) method, a technique for cross-subject alignment,increases the power of multisubject regional fMRI studies by focusingthe alignment power specifically on the ROIs (regions of interest) andnot elsewhere in the brain. First, all subjects' anatomical andfunctional scans are normalized to the Talairach atlas using AFNI.Sub-regions of the medial temporal lobe and the hippocampus (bilateralentorhinal cortex, perirhinal cortex, parahippocampal cortex,CA3/dentate region, CA1 region, and subiculum) are segmented in threedimensions on the MPRAGE scans. The labels for the CA3 region anddentate gyms (DG) are combined. The anatomically defined ROIs are thenused to calculate the ROI-LDDMM 3D vector field transformation for eachsubject using a customized template that is based on the mean of theentire sample is tested as the target. The ROI-LDDMM transformations foreach individual subject's ROIs are then applied to the fit coefficientmaps.

Group data are analyzed using a two-way Analysis of Variance (ANOVA)with trial types and group as fixed factors, and subject as a randomfactor nested within group. A liberal peak threshold of p<0.05, alongwith a spatial extent threshold of 10 voxels are used to definefunctional ROIs on the overall F statistic. This approach, rather thanusing a direct pair-wise contrast, reduces voxel selection biasesbecause any differences amongst the various conditions allows for avoxel to be selected. This threshold is then combined with theanatomical segmentations to only include voxels inside the regions ofinterest. This serves to exclude voxels that do not change with any ofthe model's factors, effectively limiting the analysis to voxels showingany changes with task condition or group. Voxels within each functionalROI are collapsed for further analysis.

Cognitive Tests During fMRI Scans at Visits 1 and 2

The activity of the subject's medial temporal lobe is measured byfunctional MRI during the subject's participation in an explicit3-alternative forced choice task, where participants view novel,repeated and similar (“lure”) stimuli. The Psychophysics Toolboxextensions in Matlab 7.0 (The MathWorks, Natick, Mass.) is used forstimulus presentation and behavioral data collection. Stimuli are colorphotographs of common objects. Each participant undergoes a series oftesting runs during the functional imaging sessions, each run consistingof a mix of three types of image pairs: similar pairs, identical pairsand unrelated foils. These image pairs are fully randomized throughoutthe run and presented individually as a series of images (see FIG. 10A).Participants are instructed to make a judgment as to whether each objectseen is new, old or similar. Of critical interest are the participants'responses when presented with the second of the pair of similar objects(the “lure”; see FIG. 10B). The correct identification by the subject oflure stimuli as “similar,” provides behavioral evidence of patternseparation, i.e., the separation of similar experiences into distinctnon-overlapping representations. However, an incorrect identification oflure stimuli as “old” or “new,” indicates a failure of patternseparation. Identification of lure stimuli as “old” indicates that thesubject is focused on the similarities between the lure stimulus and theearlier-shown partner image. Identification of the lure stimulus as“new” indicates that the subject fails to recall the earlier-shownpartner image altogether. Each run also contains a number of baselinetrials that use a challenging perceptual discrimination task which isknown to provide a lower and more-stable estimate of baseline activityin the medial temporal lobe (Stark & Squire, 2001 PNAS; Law et al,2005).

A survey of the activity level of various subregions in the medialtemporal lobe during the cognitive test, which is measured by fMRI,shows that aMCI subjects have hyperactive DG/CA3 regions and ahypoactive entorhinal cortex during the performance of memory tasks, incomparison to age-matched control subjects.

We assess the level of activity in DG/CA3 during successful memoryjudgments in control and aMCI subjects. The mean activity is calculatedfrom the average activity, which is measured by fMRI, during thepresentation of lure stimuli correctly identified by subject as“similar” that is calibrated for baseline activity. FIG. 8A shows thataMCI patients exhibit DG/CA3 hyperactivity when making these judgments(p=0.013). FIG. 8B, however, shows that treatment with levetiracetamreduces DG/CA3 hyper-activity in aMCI subjects (p=0.037). The activitylevel in the aMCI subject treated with the drug, in fact, is normalizedto the extent that that it is statistically indistinguishable from theactivity of control subjects treated with placebo. See FIG. 8C for themean activity values shown in FIGS. 8A and 8B.

The activity level during successful memory judgments in EC issignificantly lower in placebo-treated aMCI subjects in comparison tocontrols (p=0.003). See FIG. 9A. However, levetiracetam treatmentnormalizes activity in aMCI subjects in EC as well. See FIG. 9B.Levetiracetam treatment increases EC activity during memory judgments inaMCI subjects, such that it is statistically indistinguishable fromplacebo-treated control subjects. See FIG. 9B. See FIG. 9C for the meanactivity values shown in FIGS. 9A and 9B.

The normalization of DG/CA3 and EC activity during memory judgments bylevetiracetam treatment is mirrored in the change seen in the aMCIsubjects' performance in the cognitive task. With placebo treatment,aMCI patients perform worse than control subjects, correctly identifyinglure items as “similar” less often and incorrectly identifying them as“old” more often (p=0.009). See FIG. 11. However, the performance ofaMCI subjects improves significantly under levetiracetam treatment. SeeFIG. 12. The interaction of more correct “similar” identifications withless incorrect “old” identifications under drug treatment results in asignificant improvement in the performance of this memory task(p=0.039). See FIG. 13 for a table of the data represented in FIGS. 11and 12.

The performance of control-placebo subjects and aMCI subjects with drugor placebo treatment is also compared in other common cognitive tests,such as the Buschke Selective Reminding Test—Delayed Recall (FIGS. 14Aand 14B), the Benton Visual Retention Test (FIGS. 15A and 15B), VerbalPaired Associates Test—Recognition (FIGS. 16A and 16B) and Verbal PairedAssociates Test—Delayed Recall (FIGS. 17A and 17B). In all of thesetests, aMCI subjects who are treated with placebo perform worse thancontrol subjects who are treated with placebo, and levetiracetamtreatment fails to rescue performance in aMCI subjects.

There are a number of possible reasons why levetiracetam treatment doesnot help aMCI subjects with performance in these other cognitive tests.The explicit 3-alternative forced choice task that is done in the fMRIstudy is a task that is especially sensitive to DG/CA3 function. Assuch, the performance of the subjects in this task may be particularlyattuned to the changes in DG/CA3 activity resulting from levetiracetamtreatment. Further, the aMCI subjects are treated with levetiracetam foronly two weeks prior to the administration of the cognitive tests. It iscontemplated that a treatment duration of longer than two weeks, e.g.,16 weeks or 8 months, will result in improved efficacy. Finally,comparative animal studies (see Example 2) indicate that an even lowerdose would be more effective. The human dosage of 125 mg twice a day isequivalent (HED) to a rat dosage of 22.3 mg/kg/day. As is shown inExample 2 and FIG. 3, 20 mg/kg levetiracetam is too high a dose in rats,and it fails to improve the performance of AI rats in the radial mazetask. The effective doses of levetiracetam that are used in the animalmodel in Example 2 are 5-10 mg/kg. The human equivalent dose (HED) ofthe optimal rat dose in Example 2 is 0.8-1.6 mg/kg/day. Such a dosagewould result in the administration of 28-56 mg twice a day (which issubstantially lower than the 125 mg twice a day that is used in thisstudy). Thus, it is contemplated that aMCI subjects will exhibit afurther normalization of DG/CA3 and EC activity, as well as furtherimproved performance in cognitive tests, if they are treated with lowerdoses equivalent to the effective doses in rat, e.g., 25-60 mg twice aday of levetiracetam.

The HED calculation is based on body surface area. As a result, it is anestimate of what human dose corresponds to an animal (e.g., rat) dose inthe context of a maximum safe starting dose for clinical trials inhumans. Calculating the HED is typically an initial step in carrying outthe clinical trial of a drug in humans. It is not an indication of theultimate human therapeutic dose. See, “Estimating the Safe Starting Dosein Clinical Trials for Therapeutics in Adult Health Volunteers, December2002, Center for Biologics Evaluation and Research.” Blood/plasma levelsare a far better predictor of therapeutic dose correspondence betweenanimals (e.g., rats) and humans. As described below in Example 7, theactual levetiracetam blood levels of its daily doses in the aMCI patienthuman clinical studies (62.5 mg BID, 125 mg BID, and 250 mg BIDlevetiracetam doses) (see FIGS. 27A, 27B and 27C) and the actuallevetiracetam blood levels of its daily doses of 10 mg/kg and 60 mg/kgin the AI rat experiments are evaluated. The levetiracetam blood levelof its daily doses of 5 mg/kg and 20 mg/kg in the AI rats can beestimated by extrapolation. The therapeutically effective rat and humandoses produce similar rat and human levetiracetam blood levels.Likewise, the non-therapeutically effective rat and human doses producesimilar rat and human levetiracetam blood levels. Compare Humans: 7.9mcg/ml (250 mg BID) with Rats: 7.6 mcg/ml (20 mg/kg). Based on the bloodlevels, the therapeutically effective human doses that correspond to theeffective rat dose in Example 2 (i.e., 5-10 mg/kg/day) are estimated tobe 1.6-3.3 mg/kg/day. Such a dosage would result in the administrationof 56-115 mg twice a day. Example 4 confirms that aMCI subjects exhibita further normalization of DG/CA3 and EC activity, as well as furtherimproved performance in cognitive tests when they are treated with 62.5mg BID levetiracetam (i.e., a therapeutically effective dose that fallswithin 56-115 mg twice a day).

Example 4 Effect of Levetiracetam in Human Subjects with aMCI

A within-subjects trial of 8 weeks duration, involving 38 amnestic MCI(aMCI) subjects and 17 age-matched controls with a low dose treatment oflevetiracetam is conducted. During the course of the study, each aMCIsubject receives both drug and placebo treatments separately in twoperiods of two weeks each, with the order of treatments among differentaMCI subjects being counterbalanced (see FIG. 7). Age-matched controlsubjects are treated with placebo to serve as a further control.Cognitive testing and fMRI imaging data are obtained from the subjectsafter each two-week period of drug/placebo treatment.

Participants and Clinical Characterization

38 right-handed aMCI patients are recruited from the Alzheimer's DiseaseResearch Center (ADRC) at the Johns Hopkins Hospital and otherreferrals. An additional 17 right-handed healthy volunteers arerecruited from the pool of control participants in the ADRC and otherreferrals. All participants are administered the Telephone Interview ofCognitive Status to determine if they are likely to pass the entrycriteria of the study (including criteria for MRI scanning) Allparticipants further undergo neurological, psychiatric, andneuropsychological examination using standardized instruments andmethods. The psychiatric evaluation includes administration of theStructured Clinical Interview for DSM-IV Axis I Disorders and theClinical Dementia Rating (CDR) scale. All aMCI patients have CDR scoresof 0.5. Diagnosis of aMCI is based on the criteria proposed by Petersenet al. (e.g., “Mild cognitive impairment: Aging to Alzheimer's Disease,”Oxford University Press, N.Y. (2003), which include a memory complaint(corroborated by an informant), impaired memory function on testing(generally 1.5 standard deviations below the norm and at least 1standard deviation below the norm), otherwise preserved cognitivefunctioning (within 1 standard deviation of norm), no decline infunctional ability, and no dementia. Final aMCI diagnoses are reached byclinical consensus. Exclusion criteria include major neurological orpsychiatric disorders, head trauma with loss of consciousness, historyof drug abuse or dependency, and general contraindications to an MRIexamination (e.g. cardiac pacemaker, aneurysm coils, claustrophobia).Each aMCI subject is required to have a study partner (i.e., aninformant) who can provide information about the subject's dailyfunction and assure that medications are taken appropriately.

Study Visits:

The study consists of 4 visits over the course of 8 weeks (see FIG. 7).The Baseline Visit is for the purpose of performing medical,neurological, psychiatric, and neurocognitive assessments. Visits 1 and2 are identical to the Baseline Visit but include an fMRI session. TheWashout Visit, at the end of a 4 week washout period, is for the purposeof a brief clinical assessment and initiation of the second drug/placebophase.

Baseline Visit:

At the screening visit, informed consent is obtained from the subject(and an informant in the case of MCI subjects). The subject and theinformant participate in a standardized clinical interview that is usedto determine the degree of the subject's functional impairment in dailylife, based on the Clinical Dementia Rating (CDR) scale. The subject'smedical, neurological, and psychiatric history is obtained (including areview of current medications), as well as the family history ofdementia. Brief medical, neurological and psychiatric exams areconducted (including vital signs). Blood is drawn in order to performstandard laboratory tests that are needed to determine if the subjectmeets the entry criteria. The subject is re-screened forcontraindications to MRI scanning, using the standard form employed atthe Kirby Imaging Center. Brief cognitive testing is performed(described in section on neuropsychological assessment below). Theseassessments are used to determine if the subject meets the entrycriteria. All of the foregoing are completed using standardized forms.If the subject meets entry criteria for the study, the subject israndomly assigned to either the 62.5 mg BID or 250 mg BID study groupand given the study medication (drug or placebo, randomly selected), andinstructions about how it should be taken. The subject is advised aboutthe potential for having suicidal thoughts and advised to stop takingthe medication and immediately contact the study physician if thisoccurs.

Visit 1:

At the end of the first drug/placebo period 2 weeks after the BaselineVisit, the medical, neurological and psychiatric evaluations andcognitive testing are repeated. The subject is also clinically evaluatedfor suicidal ideation. Blood is drawn again to repeat the standard testsand to determine whether there are any changes related to drugtreatment; the subject's blood levetiracetam level is also obtained. Allmedication that is dispensed at the Baseline Visit (drug or placebo) iscollected and subject compliance with the medication regimen isassessed. The first fMRI session (with cognitive tests) is conducted onthe same day, either immediately before or immediately after theclinical assessment. Subjects discontinue first period treatment at thisvisit.

Washout Visit:

At the end of a washout period (4 weeks) following Visit 1, the subjectreceives a brief medical screening, including a medical and psychiatricevaluation. Blood is drawn to obtain the blood levetiracetam level (toconfirm washout). The subject is provided with new medication (drug orplacebo, alternated from what is assigned in the previous treatmentperiod) for the final phase of the study with instructions about how itshould be taken.

Visit 2:

At approximately 2 weeks after the Washout Visit (i.e., 2 weeks afterstarting the second treatment period), the medical, neurological andpsychiatric evaluations and the cognitive testing are repeated. Thesubject is clinically evaluated for suicidal ideation. Blood is drawnagain to repeat the standard tests and to determine whether there areany changes related to drug treatment; the subject's blood levetiracetamlevel is also obtained. All medication being dispensed at the WashoutVisit is collected and subject compliance with the medication regimen isassessed. The second fMRI session (with cognitive tests) is repeated onthe same day, either immediately before or immediately after theclinical assessment.

Neuropsychological Assessment

All participants undergo neuropsychological evaluation at the time ofassessment for treatment efficacy (Visits 1 and 2), as well as at theBaseline Visit. The evaluation occurs outside of the scanner andincludes the Buschke Selective Reminding Test (Buschke and Fuld, 1974)and the Verbal Paired Associates subtest, the Logical Memory subtest,the Visual Reproduction subtest of the Wechsler Memory Scale-Revised(WMS-R) (Wechsler, 1997), and the Benton Visual Retention Test, as thesetasks are particularly sensitive to medial temporal lobe function andearly memory problems (Marquis et al., 2002 and Masur et al., 1994).Additionally, subjects are asked to complete tests of more generalcognitive function such as tests to assess general mental status,executive function, attention and general naming ability. Allneuropsychological tests are administered by a trained researchassistant during a 60-minute session. As the three neuropsychologicalassessments in this study occur within a time period of 8 weeks,different versions of the neuropsychological tests are used to minimizetest specific practice effects. Breaks are provided to the subject asneeded.

Drug Administration

As described above, the drug treatment period is the two weeks precedingVisit 1 or 2 (with the two week period preceding the other Visit beingthe placebo phase). For the subjects receiving the 250 mg BID (BIDstands for twice daily) drug treatment, two 250 mg tablets oflevetiracetam are used to achieve a dose of 250 mg twice a day, i.e.,500 mg/day, which is approximately 7.1 mg/kg/day (assuming an averageadult human weight of 70 kg). For the subjects receiving the 62.5 mg BIDdrug treatment, a quarter of a scored 250 mg tablet of levetiracetam isused to achieve a dose of 62.5 twice a day, i.e., 125 mg/day which isapproximately 1.5 mg/kg/day.

All drug and placebo preparations are performed on a 1:1 allocation. Thepharmacy randomizes patients to drug dose and condition as they enroll,and keep a list of drug assignment.

Levetiracetam is rapidly and almost completely absorbed after oraladministration, and its bioavailability is not affected by food. Plasmahalf-life of levetiracetam is approximately 7±1 hour (expected to be9-10 hours in elderly due to decreased renal function). Absorption israpid, with peak plasma concentrations occurring about 1 hour followingoral administration. Steady state can be achieved after 2 days ofmultiple twice-daily dosing.

A typical starting dose of levetiracetam in treating epilepsy in humansis 500 mg twice a day, which is approximately 14.3 mg/kg/day. The dosageis then is increased until optimal efficacy, typically up to 50mg/kg/day. Thus, the 250 mg

BID dose (500 mg/day) that is used in this experiment is one-half of thelowest human dose used for treating epilepsy. The 62.5 mg BID dose (125mg/day) is one eighth of the lowest human dose used for treatingepilepsy.

MRI Data Acquisition

Imaging data are obtained through high-resolution methods developed inthe Stark laboratory. Data are collected on a Phillips 3 Tesla scanner(Eindhoven, The Netherlands) equipped with an 8-channel SENSE(Sensitivity Encoding) head coil, located at the F.M. Kirby ResearchCenter for Functional Brain Imaging at the Kennedy Krieger Institute(Baltimore, Md.). High-resolution echo-planar images are collected usingan acquisition matrix of 64×64, a repetition time of 1500 milliseconds,an echo time of 30 milliseconds, a flip angle of 70 degrees, a SENSEfactor of 2, and an isotropic resolution of 1.5 mm×1.5 mm×1.5 mm with nogap. Nineteen oblique slices are acquired parallel to the principallongitudinal axis of the hippocampus and covered the entire medialtemporal lobe region bilaterally. In addition to the functional runs, awhole-brain MPRAGE structural scan (parameters: 231 oblique slices, 0.65mm isotropic resolution) is acquired.

Image Analysis

Data analysis is carried out using the Analysis for FunctionalNeuroimages (AFNI, release 2010 10 19 1028) software. Images are firstco-registered to correct for within- and across-scan head motion.Acquisitions in which a significant motion event occur (more than 3degrees of rotation or 2 mm of translation in any direction relative toprior acquisition), plus and minus one time repetition for 1.5 seconds,are excluded from the analyses. Structural anatomical data areregistered to standard stereotaxic space (Talairach & Tournoux, 1988),and the same parameters are subsequently applied to the functional data.Behavioral vectors are produced to model different trial types.

The ROI-LDDMM (large deformation diffeomorphic metric mapping of theregion of interest) method, a technique for cross-subject alignment,increases the power of multisubject regional fMRI studies by focusingthe alignment power specifically on the ROIs (regions of interest) andnot elsewhere in the brain. First, all subjects' anatomical andfunctional scans are normalized to the Talairach atlas using AFNI.Sub-regions of the medial temporal lobe and the hippocampus (bilateralentorhinal cortex, perirhinal cortex, parahippocampal cortex,CA3/dentate region, CA1 region, and subiculum) are segmented in threedimensions on the MPRAGE scans. The labels for the CA3 region anddentate gyms (DG) are combined. The anatomically defined ROIs are thenused to calculate the vector field transformation for each subject usingthe Advanced Normalization Tools (ANTs) software package and acustomized template that is based on the mean of the entire sampletested as the target. The resulting vector transformations for eachindividual subject's ROIs are then applied to the fit coefficient maps.

Group data are analyzed using a two-way Analysis of Variance (ANOVA)with trial types and group as fixed factors, and subject as a randomfactor nested within group. A liberal peak threshold of p<0.07, alongwith a spatial extent threshold of 40 voxels are used to definefunctional ROIs on the overall F statistic. This approach, rather thanusing a direct pair-wise contrast, reduces voxel selection biasesbecause any differences amongst the various conditions allows for avoxel to be selected. This threshold is then combined with theanatomical segmentations to only include voxels inside the regions ofinterest. This serves to exclude voxels that do not change with any ofthe model's factors, effectively limiting the analysis to voxels showingany changes with task condition or group. Voxels within each functionalROI are collapsed for further analysis.

Cognitive Tests During fMRI Scans at Visits 1 and 2

The activity of the subject's medial temporal lobe is measured byfunctional MRI during the subject's participation in an explicit3-alternative forced choice task, where participants view novel,repeated and similar (“lure”) stimuli. The Psychophysics Toolboxextensions in Matlab 7.0 (The MathWorks, Natick, Mass.) is used forstimulus presentation and behavioral data collection. Stimuli are colorphotographs of common objects. Each participant undergoes a series oftesting runs during the functional imaging sessions, each run consistingof a mix of three types of image pairs: similar pairs, identical pairsand unrelated foils. These image pairs are fully randomized throughoutthe run and are presented individually as a series of images (see FIG.10A). Participants are instructed to make a judgment as to whether eachobject seen is new, old or similar. Of critical interest are theparticipants' responses when they are presented with the second of thepair of similar objects (the “lure”; see FIG. 10B). The correctidentification by the subject of lure stimuli as “similar,” providesbehavioral evidence of pattern separation, i.e., the separation ofsimilar experiences into distinct non-overlapping representations.However, an incorrect identification of lure stimuli as “old” or “new,”indicates a failure of pattern separation. Identification of lurestimuli as “old” indicates that the subject focused on the similaritiesbetween the lure stimulus and the earlier-shown partner image.Identification of the lure stimulus as “new” indicates that the subjectfails to recall the earlier-shown partner image altogether. Each runalso contains a number of baseline trials that use a challengingperceptual discrimination task is known to provide a lower andmore-stable estimate of baseline activity in the medial temporal lobe(Stark & Squire, 2001 PNAS; Law et al, 2005).

A survey of the activity level of various subregions in the medialtemporal lobe during the cognitive test, which is measured by fMRI,shows that aMCI subjects have hyperactive DG/CA3 regions and ahypoactive entorhinal cortex during the performance of memory tasks, incomparison to age-matched control subjects.

We assess the level of activity in DG/CA3 during successful memoryjudgments in control and aMCI subjects. The mean activity is calculatedfrom the average activity, which is measured by fMRI, during thepresentation of lure stimuli that are correctly identified by subject as“similar” that is calibrated for baseline activity. FIGS. 22A and 22Bshow that aMCI patients in both the 62.5 mg BID cohort (N=20) and 250 mgBID cohort (N=17) exhibit DG/CA3 hyperactivity when making thesejudgments (p=0.0041 and p=0.0466 respectively). Treatment withlevetiracetam does not significantly reduce the DG/CA3 hyperactivity inaMCI subjects in the 250 mg BID cohort or the 62.5 mg BID cohort.However, treatment with levetiracetam in the 62.5 mg BID cohort reducesthe DG/CA3 hyperactivity in aMCI subjects as compared to placebocontrol. No such improvement is observed in the 250 mg BID cohort.

We also assess the effect on cognition of levetiracetam using lure-basedbehavior performance. With placebo treatment, aMCI patients performworse than control subjects, correctly identifying lure items as“similar” less often and incorrectly identifying them as “old” moreoften in both the 62.5 mg BID cohort and the 250 mg BID cohort. SeeFIGS. 23A and 23B. However, the performance of aMCI subjects improvessignificantly under 62.5 mg BID levetiracetam treatment. See FIG. 24A.The interaction of more correct “similar” identifications with lessincorrect “old” identifications under drug treatment results in asignificant improvement in the performance of this memory task(p=0.041). The performance of aMCI subjects does not significantlyimprove under 250 mg BID levetiracetam treatment (p=0.2396). See FIG.24B.

Example 5 Effect of Brivaracetam and Seletractam in Aged-Impaired RatsSubjects

Aged, male Long-Evans rats are obtained at 8-9 month of age from CharlesRiver Laboratories (Raleigh, N.C.) and housed in a vivarium at JohnsHopkins University until 24-26 month of age. Young rats obtained fromthe same source are housed in the same vivarium and tested at 6 monthsof age. All rats are individually housed at 25° C. and maintained on a12 hr light/dark cycle. Food and water are provided ad libitum unlessnoted otherwise. The rats are examined for health and pathogen-freestatus throughout the experiments, as well as necropsies at the time ofsacrifice. All procedures in the current investigations are approved bythe Institutional Animal Care and Use Committee in accordance with theNational Institutes of Health directive.

Background Characterization of Cognitive Status

All rats are screened in a standardized assessment of spatial cognitionprior to the studies with experimental treatments. That backgroundassessment uses a well-established Morris Water Maze (“MWM”) protocol.The MWM protocol is substantially the same as the one described inExample 1. See, also, Gallagher et al., Behav. Neurosci. 107:618-626,(1993). Briefly, the rats are trained for eight days (three trials perday) to locate a camouflaged escape platform that remained at the samelocation throughout training in a water maze. Every sixth trial consistsof a probe trial (free swim with no escape platform) that serves toassess the development of a spatially localized search for the escapeplatform. During these probe trials, a learning index is generated fromthe proximity of the rat to the escape platform and is used to defineimpairment in the aged rats. The learning index is the sum of weightedproximity scores obtained during probe trials, with low scoresreflecting a search near the escape platform and high scores reflectingsearches farther away from the platform (Gallagher et al, 1993). Cuetraining (visible escape platform) occurs on the last day of training totest for sensorimotor and motivational factors independent of spatiallearning. Aged rats with impaired spatial memory performance (i.e.,those with learning index scores outside the young “normative” range)but successful cued training performance are characterized asAged-Impaired rats (i.e., AI rats). The AI rats are used for the studiesas described below.

Treatments

The radial arm maze experiments uses acute administration ofseletracetam (0-4 mg/kg), brivaracetam (0-4 mg/kg), or saline vehiclegiven by intraperitoneal injection (in a volume of 1 ml/kg) 30-40 minprior to test sessions. In the chronic treatment experiment,memory-impaired aged rats are implanted subcutaneously in theintrascapular region with osmotic mini-pumps (ALZET, Durect Corporation,Cupertino, Calif.) with brivaracetam (2 mg/kg/day) or saline vehiclestarting two weeks prior to assessment in the water maze.

Behavioral Assessment in the Radial Arm Maze

A radial arm maze (RAM) task is used to assess effects of acute drugtreatment with seletracetam and brivaracetam. This protocol allowswithin-subject assessment across drugs at different doses. The radialmaze consists of eight arms projecting from each side of an octagonalcenter platform, with a food well located at the distal end of each arm.Plexiglas blocks can be positioned to prevent entry into any arm.Extra-maze cues are provided in the room surrounding the maze andillumination is provided by an overhead light.

Pre-training, as described in detail in Chappell et al.Neuropharmacology 37: 481-487, (1998), consists of habituation, standardwin-shift training, and win-shift training with delays interposedbetween information and memory test phases. Drug treatments begins twodays after the completion of pre-training Three arms are blocked at thebeginning of each trial (information phase). The identity andconfiguration of the blocked arms are varied across trials.Food-deprived rats are allowed to retrieve food reward (Kellogg's FrootLoops cereal) from the five unblocked arms. The rat is then removed fromthe maze for 2 hrs (retention interval), during which time the barrierson the blocked arms re removed allowing access to all eight arms. Ratsare then placed back onto the center platform and allowed to retrievethe remaining food rewards (memory test phase). An error consists ofreturning to an arm (all four paws on the arm) from which food hadalready been obtained. Memory-impaired aged rats (n=8 for seletracetam,and n=9 for brivaracetam) are first tested with a series of drug dosesin ascending/descending order; each dose is thus tested twice, with onewashout day in between each determination. The number of errors made inthe retention phase after the 2-hr delay is used to assess memoryperformance. See FIG. 19 and FIG. 20. A series of different doses ofbrivaracetam is tested: 0.0625 mg/kg, 0.125 mg/kg, 0.25 mg/kg, 0.5mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg. A series of different doses ofseletracetam is tested: 0.0625 mg/kg, 0.125 mg/kg, 0.25 mg/kg, 0.5mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg. As shown in FIG. 19, brivaracetamhas a significant effect as a function of dose in the range tested(repeated measures ANOVA for within-subject contrasts, F(1, 8)=6.046,p=0.039). As shown in

FIG. 20, seletracetam also has a significant effect as a function ofdose in the range tested (repeated measures ANOVA for within-subjectcontrasts, F(1, 7)=12.577, p=0.009).

Behavioral Assessment in the Water Maze

Rats are trained and tested in a novel water maze environment to assessthe effect of drug treatment. The water maze used here is housed in adifferent building and is surrounded by curtains with a novel set ofpatterns relative to the maze used for initial assessment of cognitivestatus. The training protocol consists of 6 trials per day for 2 days tolocate a submerged escape platform. On each trial, a rat is released inthe maze from one of four equally spaced starting positions around theperimeter of the pool. The starting position varies from trial to trial.If the rat does not locate the escape platform within 60 s on any trial,the experimenter guides and places the rat on the platform, where itremains for 20 s. The rat is then removed from the platform and placedin a holding cage for another 40 s before the next trial. Approximately24 hrs after the last training trial, a probe test in the absence of theescape platform is given to assess spatial memory. Results of thebehavior assessment in the Water Maze task are shown in FIG. 21A andFIG. 21B. Rats treated with brivaracetam at 2 mg/kg/day (t(2)=10.000,p=0.010) but not vehicle (t(2)=1.964, p=0.188) show a significantspatial bias for the target quadrant compared to the other controlsquadrants. In addition, brivaracetam-treated rats (2 mg/kg/day) spendsignificantly more time in the target quadrant than the vehicle-treatedrats, t(4)=3.881, p=0.018. Brivaracetam-treated rats (2 mg/kg/day) spendsignificantly more time in the target annulus (area surrounding thelocation of the escape platform) than the vehicle-treated rats,t(4)=3.109, p=0.036.

Example 6 Chronic Treatment with Levetiracetam in Aged-Impaired Rats

Subjects

Aged, male Long-Evans rats are obtained at 8-9 month of age from CharlesRiver Laboratories (Raleigh, N.C.) and housed in a vivarium at JohnsHopkins University until 24-26 month of age. Young rats obtained fromthe same source are housed in the same vivarium and tested at 6 month ofage. All rats are individually housed at 25° C. and maintained on a 12hr light/dark cycle. Food and water are provided ad libitum unless notedotherwise. The rats are examined for health and pathogen-free statusthroughout the experiments, as well as necropsies at the time ofsacrifice. All procedures in the current investigations are approved bythe Institutional Animal Care and Use Committee in accordance with theNational Institutes of Health directive.

Background Behavioral Characterization

All rats are screened in a standardized assessment of spatial cognitionprior to the studies with experimental treatments. That backgroundassessment uses a well-established Morris water maze protocol asdescribed in Gallagher et al, 1993. Briefly, the rats are trained foreight days (three trials per day) to locate a camouflaged escapeplatform that remains at the same location throughout training in awater maze. Every sixth trial consists of a probe trial (free swim withno escape platform) that serves to assess the development of a spatiallylocalized search for the escape platform. During these probe trials, alearning index is generated from the proximity of the rat to the escapeplatform and is used to define impairment in the aged rats. The learningindex is the sum of weighted proximity scores obtained during probetrials, with low scores reflecting a search near the escape platform andhigh scores reflecting searches farther away from the platform(Gallagher et al, 1993). Cue training (visible escape platform) occurson the last day of training to test for sensorimotor and motivationalfactors independent of spatial learning. Aged rats with impaired spatialmemory performance (i.e., those with learning index scores outside theyoung “normative” range) but successful cued training performance areused for the studies as described below.

Surgery and Treatments

Under isoflurane anesthesia, memory-impaired aged rats are implantedsubcutaneously in the intrascapular region with osmotic mini-pumps(ALZET,

Durect Corporation, Cupertino, Calif.) with levetiracetam (10 mg/kg/day)or saline vehicle for four weeks prior to perfusion. Young rats, whichserved as controls, receive either saline vehicle in mini-pumps or noimplantation.

Perfusion and Tissue Preparation

At the end of the 4-week treatment period, rats are anesthetized withisoflurane and perfused transcardiacally with 0.1 M phosphate buffersaline, followed by 4% paraformaldehyde in phosphate buffer. Brains areremoved and post-fixed in paraformaldehyde overnight. The brains arethen moved into 4% paraformaldehyde in phosphate buffer containing 16%sucrose. The brains are then sectioned with a freezing microtome on thecoronal plane at 40 μm and stored in either 4% paraformaldehyde at 4° C.for in situ hybridization or cryoprotectant at −20° C. forimmunohistochemistry.

Probe Synthesis

Probe templates are synthesized as described in Haberman et al. (2008).Initial primer sequences for reelin are as follows: left,agtactcagacgtgcagtgg, right, ctcatgaagcaaagtccaa; PCR products areverified by restriction endonuclease digestion. Initial PCR products areamplified further with the same PCR primers that had been modified bythe addition of T7 or SP6 RNA polymerase binding sites. PCR productscontaining T7 and SP6 extensions are purified by SVgel and a PCR cleanupkit (Promega). 35S-UTP labeled riboprobe is then generated using theMaxiscript kit (Ambion). The probe is then phenol/choloroform extractedand precipitated in ethanol at −80° C. The final probe is resuspended inRNase-free water and the specific activity is determined byscintillation counter.

In Situ Hybridization

In situ hybridization is carried out as described by Haberman et al.,(2008). Free-floating tissue sections are washed in 0.75% glycine in0.1M phosphate buffer two times, followed by a single wash in phosphatebuffer. After that, sections are reacted in Proteinase K buffercontaining 1.0 μg/ml proteinase K for 30 minutes at 37° C. Sections arethen treated with acetic anhydride solution (11.3% triethanolamine,0.25% acetic anhydride, 0.04 M acetic acid) for 10 minutes at roomtemperature. This is followed by two 15-minute washes in 2× sodiumchloride/citrate buffer (SSC buffer; 20× concentration, 3M NaCl, 0.3Msodium citrate). Next, sections are transferred to a hybridizationbuffer containing 20% formamide, 0.4×Denhardt's solution, 4% dextransulfate, and 1.6×SSC) supplemented with 0.25 mg/ml tRNA, 0.33 mg/mlsheared salmon sperm DNA, 100 mM DTT, and 1×107 cpm/ml 35S-UTP-labeledprobe for overnight reaction at 60° C. The following day, sections arewashed at 60° C. in 4×SSC/0.01M DTT and 2×SSC/50% formamide. They arethen incubated with RNase (20 μg/ml) at 37° C. for 30 min. Sections arewashed with progressively decreasing concentrations of SSC beforemounting on slides. Slides are dried overnight, exposed to aphosphoimager screen, and quantified by using ImageQuant (GEHealthcare). Digital images are acquired of entorhinal cortical sectionsfrom the same levels for all animals and the subregion of interest isoutlined and quantified. Sections are averaged to obtain a single scorefor each animal.

Immunohistochemistry

Tissue is labeled with anti-SOM antiserum (Santa Cruz Biotechnology;cat. no. SC7819-P) using an established immunoperoxidase protocol andtissue sections are processed concurrently to minimize inter-replicationvariability (Haberman et al., 2009). The anti-SOM antiserum can detectsomatostatin. Briefly, sections are washed in 0.1M phosphate-bufferedsaline (PBS) to remove cryoprotectant, and endogenous peroxidases arequenched in 0.3% H202 in PBS. After additional PBS washes, sections areblocked in 5% normal horse serum in PBS with 0.3% Triton. Sections arethen incubated with primary antibody at a dilution of 1:1600 in PBScontaining 0.15% Triton and 3% normal serum for 72 hours at 4° C. withagitation. Following primary antibody incubation, sections are washed inPBS and reacted with horse anti-goat IgG biotinylated secondary antibody(Vector Laboratories Inc., Burlingame, Calif.) diluted in PBS with 0.15%Triton and 5% normal horse serum for 45 minutes. The secondary antibodyis detected with avidin-biotin complex (ABC Elite; Vector LaboratoriesInc., Burlingame, Calif.) and the avidin-biotin complex is visualizedwith nickel-enhanced diaminobenzadine (Vector Laboratories Inc.,Burlingame, Calif.). Tissue sections are mounted onto coated slides anddried, dehydrated with increasing concentrations of ethanol, clearedwith xylene, and coverslipped using DPX mounting media.

Interneuron quantification is performed using a Zeiss Axioplan 2microscope equipped with a motorized stage. All analyses are conductedblind with regards to animal age and cognitive status. The dentate hilarregion is defined using the Paxinos and Watson rat brain atlas (1998).Dorsal hilar neuron counts are derived bilaterally from four matchedtissue sections per animal with a 40× objective lens (Bregma −3.80 mm to−4.16 mm). Neuron counts are analyzed as the total number of hilarinterneurons per hippocampal section for each rat.

Results

Somatostatin is a peptide hormone that regulates the endocrine systemand affects neurotransmission and cell proliferation via interactionwith G protein-coupled somatostatin receptors and inhibition of therelease of numerous secondary hormones. Somatostatin levels in the brainhave been shown to drop as low as 10-20% in association with aging andAlzheimer's disease progression. A four-week treatment withlevetiracetam at a dose of 10 mg/kg/day in aged-impaired rats restoresthe levels of somatostatin in DG hilus. See FIG. 25. Aged-impaired ratsthat are administered a saline vehicle rather than drug possessedsignificantly lower numbers of SOM-immunoreactive hilar neurons relativeto both young and levetiracetam treated aged rats (N=18; F2,20=15.739,p<0.001; AI-LEV vs Y, p=0.679; AI-LEV vs AI-VEH, p<0.01; AI-VEH vs Y,p<0.001).

Reelin is a large secreted extracellular matrix glycoprotein that helpsregulate processes of neuronal migration and positioning in thedeveloping brain by controlling cell-cell interactions. Reduced reelinexpression in EC2 neurons has been observed in aged rats with memoryloss, in hAPPJ20 AD mice, as well as in human AD brains (Chin et al.2007; Stranahan et al. 2010). A four-week treatment with levetiracetamat a dose of 10 mg/kg/day in aged-impaired rats restores the levels ofreelin in Entorhinal Cortex (EC2). See FIG. 26. A one-way ANOVA shows asignificant difference among the groups, F(2, 20)=5.035, p=0.017.Additional analysis shows that reelin mRNA expression in the lateralentorhinal cortex of AI rats treated with vehicle controls (AI-VEH) issignificantly lower than that of young rats, t(13)=2.790, p=0.015.Treatment with levetiracetam in AI rats at a dose of 10 mg/kg/day for 28days (AI-LEV) significantly increases the expression of reelin,t(13)=2.386, p=0.033 (compared to AI-VEH).

Example 7 Evaluation of Levetiracetam Blood Plasma Levels

Human: in the human studies described in Examples 3 and 4, a subject'slevetiracetam blood plasma level is assessed at each visit. Thesubject's blood is drawn by the Johns Hopkins Phlebotomy Service andanalysis of levetiracetam blood plasma levels is conducted either by theJohns Hopkins Core laboratory or by MedTox Laboratories in St. Paul,Minn. for the 62.5 mg BID cohort, the 125 mg BID cohort and the 250 mgBID cohort. When the levetiracetam treatment is completed, subjects inthe 62.5 mg BID cohort shows a mean levetiracetam blood plasma level of2.88 mcg/ml (SEM±0.288), while levels in the 125 mg BID had 4.4 mcg/ml(SEM±0.53) and subjects in the 250 mg BID cohort showed meanlevetiracetam blood plasma level of 7.9 mcg/ml (SEM±0.92). See FIGS.27A-27C.

Rats: Blood is drawn from aged-impaired rats by cardiac puncture duringperfusion after a 28-day levetiracetam treatment period and is sent foranalysis of levetiracetam plasma levels by MedTox Laboratories in St.Paul, Minn. Aged-impaired rats that are treated with 10 mg/kg/day oflevetiracetam shows a mean levetiracetam blood plasma level of 3.8mcg/ml (SEM±0.255), while those that are treated with 60 mg/kg/day showa mean levetiracetam blood plasma level of 22.4 mcg/ml (SEM±3.371).

The levetiracetam blood levels in the aged-impaired rats treated withdaily levetiracetam doses of 10 mg/kg and 60 mg/kg can be use toestimate the levetiracetam blood level of its daily dose of 20 mg/kg.This extrapolation gives an estimated levetiracetam blood level of 7.6mcg/ml for the 20 mg/kg daily dose. These results, together with thelevetiracetam blood levels in the three human cohorts (62.5 mg BID, 125mg BID and 250 mg BID) show that the levetiracetam blood level (3.8mcg/ml) in the aged-impaired rats treated with the 10 mg/kgtherapeutically effective daily levetiracetam dose is consistent withthe blood level of levetiracetam in the human patients who are treatedwith the therapeutically effective daily levetiracetam doses, e.g., 2.88mcg/ml (125 mg levetiracetam) and 4.4 mcg/ml (250 mg levetiracetam).These results also show that the extrapolated levetiracetam blood level(7.6 mcg/ml) in the aged-impaired rats treated with thenon-therapeutically effective 20 mg/kg daily dose is consistent with thelevetiracetam blood level (7.9 mcg/ml) in our human patients treatedwith the non-therapeutically effective daily 500 mg levetiracetam dose.

What is claimed is:
 1. A method for treating schizophrenia or bipolardisorder in a patient in need or at risk thereof, the method comprisingthe step of administering to said subject a therapeutically effectiveamount of a synaptic vesicle protein 2A (SV2A) inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof and a therapeutically effective amount of anantipsychotic or a pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof.
 2. The method of claim 1, wherein theantipsychotic is administered at a dose that is subtherapeutic ascompared to the dose at which it is therapeutically effective whenadministered in the absence of the SV2A inhibitor.
 3. The method ofclaim 1 or 2, wherein the SV2A inhibitor is selected from the group ofSV2A inhibitors referred to in International Patent ApplicationPCT/US2009/005647; International Patent Application PublicationsWO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595;WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658;WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465,549; 7,244,747;5,334,720; 4,696,943; 4,696,942; U.S. patent application Ser. Nos.12/580,464; 61/105,847; 61/152,631; and 61/175,536; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692; orpharmaceutically acceptable salts, hydrates, solvates, polymorphs, orprodrugs thereof.
 4. The method of claim 1 or 2, wherein the SV2Ainhibitor is selected from the group consisting of levetiracetam,seletracetam, and brivaracetam and derivatives, analogs,pharmaceutically acceptable salts, hydrates, solvates, polymorphs andprodrugs thereof.
 5. The method of any one of claims 1-4, wherein theSV2A inhibitor is administered every 12 or 24 hours: 1) at a daily doseof 0.001 mg/kg to 5 mg/kg, 0.0015-7 mg/kg, 0.0015-5 mg/kg, 0.01-5 mg/kg,0.05-4.0 mg/kg, 0.05-2 mg/kg, 0.05-1.5 mg/kg, 0.1-1 mg/kg, 1-5 mg/kg,1.5-4 mg/kg, or 1.8-3.6 mg/kg; or 2) at a daily dose that issubtherapeutic as compared to the dose at which it is therapeuticallyeffective when administered in the absence of the antipsychotic, whereinthe subtherapeutic daily doses are selected from the group consisting ofless than 7 mg/kg, less than 6 mg/kg, less than 5 mg/kg, less than 4mg/kg, less than 3.6 mg/kg, less than 3 mg/kg, less than 2 mg/kg, lessthan 1.5 mg/kg, less than 1.5 mg/kg, less than 1 mg/kg, less than 0.1mg/kg, less than 0.05 mg/kg, less than 0.01 mg/kg, or less than 0.0015mg/kg.
 6. The method of claim 5, wherein the SV2A inhibitor isadministered every 12 or 24 hours at a daily dose of 0.5 mg/kg to 5mg/kg.
 7. The method of claim 5, wherein the SV2A inhibitor isadministered every 12 or 24 hours at a daily dose of 0.05 mg/kg to 0.5mg/kg.
 8. The method of any one of claims 1-7, wherein the antipsychoticis selected from atypical and typical antipsychotics.
 9. The method ofclaim 8, wherein the antipsychotic is an atypical antipsychotic.
 10. Themethod of claim 9, wherein the antipsychotic is selected fromaripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone,paliperidone, quetiapine, risperidone and ziprasidone, andpharmaceutically acceptable salts, hydrates, solvates, polymorphs andprodrugs thereof.
 11. The method of claim 10, wherein the antipsychoticis selected from aripiprazole, olanzapine and ziprasidone, andpharmaceutically acceptable salts, hydrates, solvates, polymorphs, andprodrugs thereof.
 12. The method of claim 8, wherein the antipsychoticis a typical antipsychotic.
 13. The method of claim 12, wherein theantipsychotic is selected from acepromazine, benperidol, bromazepam,bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine,diazepam, dixyrazine, droperidol, flupentixol, fluphenazine,fluspirilene, haloperidol, heptaminol, isopropamide iodide,levomepromazine, levosulpiride, loxapine, melperone, mesoridazine,molindone, oxypertine, oxyprothepine, penfluridol, perazine,periciazine, perphenazine, pimozide, pipamperone, pipotiazine,prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine,sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine,tiapride, tiotixene, trifluoperazine, triflupromazine, trihexyphenidyl,and zuclopenthixol, and pharmaceutically acceptable salts, hydrates,solvates, polymorphs, and prodrugs thereof.
 14. The method of any one ofclaims 1-7, wherein the antipsychotic is a compound selected fromdopaminergic agents, glutamatergic agents, NMDA receptor positiveallosteric modulators, glycine reuptake inhibitors, glutamate reuptakeinhibitor, metabotropic glutamate receptors (mGluRs) agonists orpositive allosteric modulators (PAMs), glutamate receptor glur5 positiveallosteric modulators (PAMs), M1 muscarinic acetylcholine receptor(mAChR) positive allosteric modulators (PAMs), histamine H3 receptorantagonists, AMPA/kainate receptor antagonists, ampakines (CX-516),glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,NNOS inhibits, neurosteroids, and neurotrophic factors.
 15. The methodof any one of claims 1-7, wherein the antipsychotic is useful intreating at least one sign or symptom of schizophrenia or bipolardisorder.
 16. The method of any one of claims 1-7, wherein theantipsychotic is selected from the group of compounds referred to inU.S. Pat. Nos. 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573;5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and5,312,925, and EP Patents EP402644 and EP368388, and thepharmaceutically acceptable salts, hydrates, solvates, polymorphs, andprodrugs thereof.
 17. 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 18. The method of any one of claims 1-17, wherein theSV2A inhibitor and the antipsychotic, or their pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs, or prodrugs thereofare administered simultaneously.
 19. The method of claim 18, wherein theSV2A inhibitor and the antipsychotic, or their pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs, or prodrugs thereofare administered in a single formulation.
 20. The method of any one ofclaims 1-17, wherein SV2A inhibitor and the antipsychotic, or theirpharmaceutically acceptable salts, hydrates, solvates, polymorphs, orprodrugs thereof are administered sequentially.
 21. The method of claim20, wherein the SV2A inhibitor and the antipsychotic, or theirpharmaceutically acceptable salts, hydrates, solvates, polymorphs, orprodrugs thereof are administered in separate formulations.
 22. Themethod of any one of claims 1-21, a) wherein the SV2A inhibitor islevetiracetam or a derivative, analog, pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof and the antipsychotic isselected from aripiprazole, olanzapine and ziprasidone, andpharmaceutically acceptable salts, hydrates, solvates, and polymorphsthereof, or b) wherein the SV2A inhibitor is brivaracetam or aderivative, analog, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof and the antipsychotic is selected fromaripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, and polymorphs thereof or c)wherein the SV2A inhibitor is seletraceatm or a derivative, analog,pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof and the antipsychotic is selected from aripiprazole,olanzapine and ziprasidone, and pharmaceutically acceptable salts,hydrates, solvates, and polymorphs thereof.
 23. The method of any one ofclaims 1 to 22, wherein the treatment has a longer therapeutic effect inthe subject than is attained by administering the antipsychotic in theabsence of the SV2A inhibitor by at least about 1.5×, or 2.0×, or 2.5×,or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×,or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greaterthan about 10×.
 24. The method of any one of claims 1 to 22, wherein thetreatment has a longer therapeutic effect in the subject than isattained by administering the SV2A inhibitor in the absence of theantipsychotic by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about10×.
 25. A method of increasing the therapeutic index of anantipsychotic or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in a method of treating schizophrenia orbipolar disorder in a subject in need or at risk thereof, comprisingadministering an SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in combination with theantipsychotic or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof to said subject.
 26. The method of claim25, wherein the increase in the therapeutic index of the antipsychoticis greater than the therapeutic index of the antipsychotic whenadministered in the absence of the SV2A inhibitor by at least about1.5×, or 2.0×, or 2.5×, or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or5.5×, or 6.0×, or 6.5×, or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or9.5×, or 10×, or greater than about 10×.
 27. The method of claim 25 or26, wherein the SV2A inhibitor is selected from the group of SV2Ainhibitors referred to in International Patent ApplicationPCT/US2009/005647; International Patent Application PublicationsWO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595;WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658;WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465,549; 7,244,747;5,334,720; 4,696,943; 4,696,942; U.S. patent application Ser. Nos.12/580,464; 61/105,847; 61/152,631; and 61/175,536; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692; orpharmaceutically acceptable salts, hydrates, solvates, polymorphs, orprodrugs thereof.
 28. The method of claim 25 or 26, wherein the SV2Ainhibitor is selected from the group consisting of levetiracetam,seletracetam, and brivaracetam, and derivatives, analogs,pharmaceutically acceptable salts, hydrates, solvates, polymorphs andprodrugs thereof.
 29. The method of any one of claims 25-28, wherein theantipsychotic is selected from atypical and typical antipsychotics. 30.The method of claim 29, wherein the antipsychotic is an atypicalantipsychotic.
 31. The method of claim 30, wherein the antipsychotic isselected from aripiprazole, asenapine, clozapine, iloperidone,olanzapine, lurasidone, paliperidone, quetiapine, risperidone andziprasidone, and pharmaceutically acceptable salts, hydrates, solvates,polymorphs, and prodrugs thereof.
 32. The method of claim 31, whereinthe antipsychotic is selected from aripiprazole, olanzapine andziprasidone, and pharmaceutically acceptable salts, hydrates, solvates,and polymorphs thereof.
 33. The method of claim 29, wherein theantipsychotic is a typical antipsychotic.
 34. The method of claim 33,wherein the antipsychotic is selected from acepromazine, benperidol,bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine,cyamemazine, diazepam, dixyrazine, droperidol, flupentixol,fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamideiodide, levomepromazine, levosulpiride, loxapine, melperone,mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol,perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine,prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine,sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine,tiapride, tiotixene, trifluoperazine, triflupromazine, trihexyphenidyl,and zuclopenthixol, and pharmaceutically acceptable salts, hydrates,solvates, and polymorphs thereof.
 35. The method of any one of claims25-28, wherein the antipsychotic is a compound selected fromdopaminergic agents, glutamatergic agents, NMDA receptor positiveallosteric modulators, glycine reuptake inhibitors, glutamate reuptakeinhibitor, metabotropic glutamate receptors (mGluRs) agonists orpositive allosteric modulators (PAMs), glutamate receptor glur5 positiveallosteric modulators (PAMs), M1 muscarinic acetylcholine receptor(mAChR) positive allosteric modulators (PAMs), histamine H3 receptorantagonists, AMPA/kainate receptor antagonists, ampakines (CX-516),glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,NNOS inhibits, neurosteroids, and neurotrophic factors.
 36. The methodof any one of claims 25-28, wherein the antipsychotic is useful intreating at least one sign or symptom of schizophrenia or bipolardisorder.
 37. The method of any one of claims 25-28, wherein theantipsychotic is selected from the group of compounds referred to inU.S. Pat. Nos. 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573;5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and5,312,925, and EP Patents EP402644 and EP368388, and thepharmaceutically acceptable salts, hydrates, solvates, and polymorphsthereof.
 38. 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 39. A pharmaceutical composition comprising an SV2A inhibitorand an antipsychotic or their pharmaceutically acceptable salts,hydrates, solvates, polymorphs or prodrugs.
 40. The pharmaceuticalcomposition of claim 39, wherein the SV2A inhibitor and theantipsychotic or their pharmaceutically acceptable salts, hydrates,solvates, polymorphs or prodrugs are in separate dosage forms or in aunit dosage form.
 41. The composition of claim 39 or 40, wherein thecomposition is in a solid form, a liquid form, a suspension form, asustained release form, a delayed release form, or an extended releaseform.
 42. The composition of any one of claims 39-41, wherein the SV2Ainhibitor is selected from the group of SV2A inhibitors referred to inInternational Patent Application PCT/US2009/005647; International PatentApplication Publications WO2010/144712; WO2010/002869; WO2008/132139;WO2007/065595; WO2006/128693; WO2006/128692; WO2005/054188;WO2004/087658; WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465,549;7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. patent application Ser.Nos. 12/580,464; 61/105,847; 61/152,631; and 61/175,536; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692; orpharmaceutically acceptable salts, hydrates, solvates, polymorphs, orprodrugs thereof.
 43. The composition of any one of claims 39-41,wherein the SV2A inhibitor is selected from the group consisting oflevetiracetam, seletracetam, and brivaracetam and derivatives, analogs,pharmaceutically acceptable salts, hydrates, solvates, polymorphs andprodrugs thereof.
 44. The composition of any one of claims 39-41,wherein the SV2A inhibitor in the composition is present in an amount of0.07-350 mg, or 0.1-500 mg, 0.1-350 mg, 0.7-350 mg, 3-300 mg, 3-150 mg,3-110 mg, 7-70 mg, 70-350 mg, 100-300 mg, or 125-250 mg.
 45. Thecomposition of claim 44, wherein the SV2A inhibitor in the compositionis present in an amount of 50-250 mg.
 46. The composition of claim 44,wherein the SV2A inhibitor in the composition is present in an amount of3-50 mg.
 47. The composition of any one of claims 39-41, wherein theSV2A inhibitor is present in an amount less than 500 mg, less than 350mg, less than 300 mg, less than 250 mg, less than 200 mg, less than 150mg, less than 110 mg, less than 100 mg, less than 70 mg, less than 50mg, less than 35 mg, less than 10 mg, less than 7 mg, less than 5 mg,less than 3 mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, lessthan 0.1 mg, less than 0.07 mg or less than 0.05 mg.
 48. The compositionof any one of claims 39-47, wherein the antipsychotic is selected fromatypical and typical antipsychotics.
 49. The composition of claim 48,wherein the antipsychotic is an atypical antipsychotic.
 50. Thecomposition of claim 49, wherein the antipsychotic is selected fromaripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone,paliperidone, quetiapine, risperidone and ziprasidone, and thepharmaceutically acceptable salts, hydrates, solvates, polymorphs, andprodrugs thereof.
 51. The composition of claim 50, wherein theantipsychotic is selected from aripiprazole, olanzapine and ziprasidone,and the pharmaceutically acceptable salts, hydrates, solvates, andpolymorphs thereof.
 52. The composition of claim 48, wherein theantipsychotic is a typical antipsychotic.
 53. The composition of claim52, wherein the antipsychotic is selected from acepromazine, benperidol,bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine,cyamemazine, diazepam, dixyrazine, droperidol, flupentixol,fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamideiodide, levomepromazine, levosulpiride, loxapine, melperone,mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol,perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine,prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine,sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine,tiapride, tiotixene, trifluoperazine, triflupromazine, trihexyphenidyl,and zuclopenthixol, and the pharmaceutically acceptable salts, hydrates,solvates, and polymorphs thereof.
 54. The composition of any one ofclaims 39-47, wherein the antipsychotic is a compound selected fromdopaminergic agents, glutamatergic agents, NMDA receptor positiveallosteric modulators, glycine reuptake inhibitors, glutamate reuptakeinhibitor, metabotropic glutamate receptors (mGluRs) agonists orpositive allosteric modulators (PAMs), glutamate receptor glur5 positiveallosteric modulators (PAMs), M1 muscarinic acetylcholine receptor(mAChR) positive allosteric modulators (PAMs), histamine H3 receptorantagonists, AMPA/kainate receptor antagonists, ampakines (CX-516),glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,NNOS inhibits, neurosteroids, and neurotrophic factors.
 55. Thecomposition of any one of claims 39-47, wherein the antipsychotic isuseful in treating at least one sign or symptom of schizophrenia orbipolar disorder.
 56. The composition of any one of claims 39-47,wherein the antipsychotic is selected from the group of compoundsreferred to in U.S. Pat. Nos. 4,734,416; 5,006,528; 4,145,434;5,763,476; 3,539,573; 5,229,382; 5,532,372; 4,879,288; 4,804,663;4,710,500; 4,831,031; and 5,312,925, and EP Patents EP402644 andEP368388, and the pharmaceutically acceptable salts, hydrates, solvates,and polymorphs thereof.
 57. 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